Synthesis of resorcylic acid lactones useful as therapeutic agents

ABSTRACT

Disclosed are macrocyclic compounds of formulae I, I′, II, II′, III, III′, IV, and V, which are analogs of the pochonin resorcylic acid lactones, pharmaceutical compositions comprising the compounds, and methods and uses comprising the compounds for the treatment of diseases mediated by kinases and Heat Shock Protein 90 HSP90.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.12/863,123 filed on Jul. 15, 2010, which is a U.S. National Stageapplication of International Application number PCT/US2009/031149, filedon Jan. 15, 2009, which claims the benefit of priority to U.S.provisional application Ser. No. 61/011,163 filed Jan. 15, 2008, thedisclosures of each of which are hereby incorporated by reference intheir entireties for all purposes.

FIELD OF THE INVENTION

The present invention is directed to novel derivatives, analogs andintermediates of the natural products radicicol and the pochonins, andto their syntheses. The present invention is further directed to use ofthese compounds as inhibitors of kinases and of the enzyme family knownas heat shock protein 90 (HSP90).

BACKGROUND OF THE INVENTION

The invention claimed herein was made by or behalf of Universite deStrasbourg, Le Center national De La Recherche Scientifique, andNexGenix Pharmaceuticals Inc., who are parties to a joint researchagreement signed on Jul. 1, 2007 and related to macrocyclic compounds,such as radicicol and its derivatives, which are useful as kinase andHSP90 inhibitors.

In the mid-1950's, it was discovered that phosphorylation can reversiblyalter the function of enzymes by means of protein kinases which catalyzephosphorylation, or by protein phosphatases which are involved in thedephosphorylation step. These reactions play an essential role inregulating many cellular processes, especially signaling transductionpathways. In the late 1970's, the Rous sarcoma virus (v-Src)'stransforming factor was discovered to be a protein kinase, and alsotumor-promoting phorbol esters were found to be potent activators ofprotein kinase C, revealing the first known connection between diseaseand abnormal protein phosphorylation. Since then transductionmechanistic defects have been found to cause numerous oncogenicprocesses and to have a role in diabetes, inflammatory disorders, andcardiovascular diseases. (T. Hunter, Cell, 100:113-127 (2000); P. Cohen,Nat. Rev. Drug Discov., 1:309 (2002)). Thus selective kinase andphosphatase inhibitors have emerged as important drug targets, andinhibition of kinase phosphorylation activity is one of the mostpromising strategies for chemotherapy.

Macrocyclic resorcylic acid lactones such as radicicol and the relatedpochonins, are a structurally related group of secondary metabolitesisolated from cultures of the clavicipitaceous hyphomycete Pochoniagenus, such as Pochonia chlamydosporia var. catenulate strain P0297.See, e.g., V. Hellwig et al., J. Natural Prod., 66(6):829-837 (2003).These compounds and analogs or derivatives of the compounds have beenevaluated as kinase inhibitors or inhibitors of HSP90. Halohydrin andoxime derivatives of radicicol were prepared and evaluated for theirv-src tyrosine kinase inhibitory, antiproliferative, and antitumor invitro activity (T. Agatsuma et al., Bioorg. & Med. Chem.,10(11):3445-3454 (2002).

Like kinases, heat shock proteins (HSPs) interact with ATP and areimportant targets for controlling disease, however they have a differentmechanistic effect. Immediately after exposure to a stress such as heat,hypoxia or acidosis, cells in most tissues rapidly escalate productionrate of the HSPs. It is now believed that heat HSPs are molecularchaperones, i.e., they prevent improper associations and assist in thecorrect folding of other cellular proteins collectively termed clientsand substrates. HSP's are also found in association with tumors andother pathophysiological conditions. In fact, chaperone proteinsfacilitate the survival of tumor cells in stressful environments byfacilitating tolerance of alterations inside the cell. HSPs areubiquitous, highly conserved among the species, and usually classifiedby molecular weight to the following major families: HSP100, HSP90,HSP70, HSP60 and small HSPs. These families have structural andfunctional differences, but work cooperatively at different stages ofprotein folding. HSP90 has attracted particular attention due to itsassociation with many types of signaling molecules such as v-Src and Rafthat play a critical role in malignant transformation and metastasisdevelopment. Thus, HSP90 inhibitors are desired for designingchemotherapies, and also for elucidating the interplay in complexsignaling networks.

Heat Shock Protein 90's (Hsp90s) are ubiquitous chaperone proteins thatmaintain the proper conformation of many “client” proteins (see Kamalet. al. Trends Mol. Med. 2004, 10, 283-290; Dymock et. al. Expert Opin.Ther. Patents 2004, 14, 837-847; Isaacs et. al. Cancer Cell, 2003, 3,213; Maloney et. al. Expert Opin. Biol. Ther. 2002, 2, 3-24 and Richteret. al. J. Cell. Physiol. 2001, 188, 281-290), and are involved infolding, activation and assembly of a wide range of proteins, includingkey proteins involved in signal transduction, cell cycle control andtranscriptional regulation. Researchers have reported that HSP90chaperone proteins are associated with important signaling proteins,such as steroid hormone receptors and protein kinases, including, e.g.,Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner, TIBS,1999, 24, 136-141; Stepanova et. al., Genes Dev. 1996, 10, 1491-502; Daiet. al., J. Biol. Chem. 1996, 271, 22030-4). Studies further indicatethat certain co-chaperones, e.g., Hsp70, p60/Hop/Sti1, Hip, Bag1,HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 in itsfunction (see for example Caplan, Trends in Cell Biol., 1999, 9,262-268). Inhibition of Hsp90 causes these client proteins to adoptaberrant conformations, and these abnormally folded proteins are rapidlyeliminated by the cell via ubiquitinylation and proteasome degradation.Interestingly, the list of Hsp90 client proteins includes a series ofnotorious oncogenes. Four of them are clinically validated cancertargets: HER-2/neu (Herceptin® (trastuzumab)), Bcr-Abl (Gleevec®(imatinib mesylate)), the estrogen receptor (tamoxifen), and theandrogen receptor (Casodex® (bicalutamide)), while the others play acritical role in the development of cancer. Some of the most sensitiveHsp90 clients are involved in growth signaling (Raf-1, Akt, cdk4, Src,Bcr-Abl, etc). In contrast, few tumor suppressor genes, if any, seem tobe clients of Hsp90 (for lists of client proteins see Pratt et. al. Exp.Biol. Med. 2003, 228, 111-133; Workman et. al. Cancer Lett. 2004, 206,149-157 and Zhang et. al. J. Mol. Med. 2004, 82, 488-499.), andconsequently, inhibition of Hsp90 has an overall anti-proliferativeeffect. In addition, some client proteins are involved in otherfundamental processes of tumorigenesis, namely apoptosis evasion (e.g.Apaf-1, RIP, Akt), immortality (e.g. hTert), angiogenesis (e.g. VEGFR,Flt-3, FAK, HIF-1), and metastasis (c-Met).

The numerous client proteins of HSP90 play a crucial role in growthcontrol, cell survival and development processes, and those clients areknown to include receptor tyrosine kinases, serine/threonine kinases,steroid hormone receptors, transcription factors and telomerase.

In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitorshave also been implicated in a wide variety of other utilities,including use as anti-inflammation agents, anti-infectious diseaseagents, agents for treating autoimmunity, agents for treating ischemia,and agents useful in treating neurodegenerative diseases and inpromoting nerve regeneration (see M. Waza et al, Nature Med. 11:1088(2005); Rosen et al., WO 02/09696; PCT/US01/23640; Degranco et al., WO99/51223; PCT/US99/07242; Gold, U.S. Pat. No. 6,210,974 BI). There arereports in the literature that fibrogenetic disorders including but notlimited to scleroderma, polymyositis, systemic lupus, rheumatoidarthritis, liver cirrhosis, keloid formation, interstitial nephritis,and pulmonary fibrosis may be treatable. (Strehlow, WO 02/02123;PCT/US01/20578).

Some resorcylic acid lactones have been found to inhibit HSP90, thusnatural products radicicol and geldanamycin (P. Delmotte and J.Delmotte-Plaquee, Nature (London), 171:344 (1953); and C. DeBoer et al.,J Antibiot (Tokyo), 23:442 (1970), respectively) were shown to suppressthe transformed phenotype of cell expressing activated Src (H. J. Kwonet al., Cancer Research, 52:6926 (1992); Y. Uehara et al., Virology,164:294 (1988)). Related compounds such as herbimycin have been reportedto have similar effects (S. Omura et al., J Antibiot (Tokyo), 32:255(1979).

Other resorcylic acid lactones (RALs) studied in this respect include17-allylamino-17-demethoxygeldanamycin (17AAG) (D. B. Solit et al.,Clin. Cancer Res., 8:986 (2002); L. R. Kelland et al., J. Natl. CancerInst., 91:1940 (1999)); 17DMAG (J. L. Eiseman et al., Cancer Chemother.Pharmacol., 55:21-32 (2005)); IPI-504 (J. Ge et al., J. Med. Chem.,49:4606 (2006); oxime derivatives such as KF25706 (S. Soga, et al.,Cancer Res., 59:2931 (1999)) and KF55823 (S. Soga et al., CancerChemotherapy and Pharmacology, 48:435 (2001)); and Danishefsky et al.'scycloproparadicicol (A. Rivkin et al., Ibid., 44:2838 (2005)).Structurally related variants include chimeric inhibitors havingradicicol's carboxyresorcinol and the geldanamycin's benzoquinone (R. C.Clevenger and B. S. Blagg, Org. Lett., 6:4459 (2004); G. Shen and B. S.Blagg, Ibid. 7:2157 (2004); G. Shen et al., J. Org. Chem., 71:7618(2006)).

Radicicol-Based HSP90 Inhibitors

Considerable interest in radicicol's medicinal applications has followedthe initial findings. (See U.S. Pat. No. 6,946,456; and U.S. PatentApplication Publication Nos. 2003-0211469, 2004-0102458, 2005-0074457,2005-0261263, 2005-0267087, 2006-0073151, 2006-0251574, 2006-0269618,2007-0004674, and 2007-0010432).

Strikingly, some resorcylic macrolides that are close analogs ofradicicol are known to inhibit kinases but not HSP90. Indeed, LL-Z1640-2was found to be a potent and selective inhibitor of TAK1 kinase forwhich radicicol and other resorcylides were not active. (J.Ninomiya-Tsuji et al., J. Biol. Chem., 278:18485 (2003); P. Rawlins etal., Int. J. Immunopharma., 21:799 (1999); K. Takehana et al., Biochem.Biophys. Res. Comm., 257:19 (1999); A. Zhao et al., J. Antibiotics,52:1086 (1999)). Closely related LL-783,227, where one of the olefinshas been reduced, is a potent inhibitor of MEK kinase. (A. Zhao et al.,J. Antibiotics 52:1086 (1999)). Compound F87-2509.04 was found to inducedegradation of mRNA containing AU-rich elements (ARE) (T. Kastelic etal., Cytokine, 8:751 (1996)) and hypothemycin was found to inhibit theRas-mediated cellular signaling. (H. Tanaka et al., Jap. J. Cancer Res.,90:1139 (1999)). It has been shown that aigialomycin D is a CDKinhibitor. (S. Barluenga et al., Angew. Chem., Int. Ed., 46(24):3951(2006)).

Other close analogs of radicicol do inhibit HSP90. Pochonin D is apotent inhibitor of HSP90. (E. Moulin et al., J. Am. Chem. Soc.,127(19):6999 (2005)). And pochonin A has been reported to be a 90 nMinhibitor of HSP90. Pochonin C was found to be an inhibitor of herpes'helicase-primase, which is an ATPase rather than a kinase. (V. Hellwiget al., J. Nat. Prod., 66:829 (2003)). Although radicicol and pochonin Care structurally very similar, they have very different conformations insolution, and different biological activities. (S. Barluenga et al.,Chem. Eur. J., 11:4935 (2005). Thus it appears the “floppiness” of themacrocyclic may play an essential role in inhibitory differences amongresorcylic acid macrolides, and in any case makes those effectsdifficult to predict by theoretical methods.

Some resorcylic acid macrolides had been known as kinase or phosphataseinhibitors (U.S. Pat. Nos. 5,674,892; 5,728,726; 5,731,343; and5,795,910), or to inhibit other enzymes (U.S. Pat. No. 5,710,174inhibiting FXIIIa catalysis of fibrin cross-linking). Resorcylic acidmacrolides were also employed for other medical indications (U.S. Pat.Nos. 3,453,367; 3,965,275; 4,035,504; 4,670,249; 4,778,821; 4,902,711;and 6,635,671).

Radicicol and the pochonins are natural products; intermediates forsynthesizing some of their analogues of them may be obtained byfermentation, however relying only upon those natural products or theirfermentation derivatives severely limits the range of compounds. Thus anumber of novel resorcylic acid macrolides have been synthesized. Manyof these are zearalane and related compounds in which the macrocyclicring contains no carbon-carbon double bond other than between carbons ofthe phenyl ring. (U.S. Pat. Nos. 3,373,038; 3,586,701; 3,621,036;3,631,179; 3,687,982; 3,704,249; 3,751,431; 3,764,614; 3,810,918;3,836,544; 3,852,307; 3,860,616; 3,901,921; 3,901,922; 3,903,115;3,957,825; 4,042,602; 4,751,239; 4,849,447; and 2005-0256183). Syntheseshave also been reported for resorcylic acid macrolides characterized byone double bond between ring carbons outside the phenyl ring. (U.S. Pat.Nos. 3,196,019; 3,551,454; 3,758,511; 3,887,583; 3,925,423; 3,954,805;and 4,088,658). Most of those are 14-member macrocycles, but syntheseshave also been reported for the 12-member macrocycle analogs. (U.S. Pat.Nos. 5,710,174; 6,617,348; and 2004-0063778, and PCT publication no. WO02/48135)

Syntheses have also been reported for radicicol-related compounds havingtwo non-aromatic double bonds and either a halide or a 1,2-oxo group(i.e., an epoxide) on the macrocyclic ring. (U.S. Pat. Nos. 4,228,079;5,597,846; 5,650,430; 5,977,165; 7,115,651; and Japanese patent documentnos. JP 6-279279A, JP 6-298764A, JP 9-202781A, JP 10-265381A2; and JP2000-236984). Syntheses of oximes of radicicol-related compounds aredisclosed in U.S. Pat. Nos. 5,977,165; 6,239,168; 6,316,491; 6,635,662;2001-0027208; 2004-0053990; Japanese patent document no. JP2003-113183A2; and PCT publication no. WO 99/55689 Synthesis ofcyclopropa-analogs of radicicol is disclosed in U.S. Pat. No. 7,115,651and PCT Publication No. WO 05/061481. Syntheses of some other resorcylicacid macrolide analogs are disclosed in U.S. patent publication no.2006-0247448 and in PCT publication no. WO 02/48135. Radicicol as wellas Pochonins A and C have also been synthesized. (S. Barluenga et al.,Angew. Chemie, 43(26):3467-3470 (2004); S. Barluenga et al., Chemistry—AEuropean Journal, 11(17):4935-4952 (Aug. 19, 2005); E. Moulin et al., etal., Organic Letters, 7(25):5637-5639 (Dec. 8, 2005).

U.S. Pat. No. 7,115,651 to Danishcfsky et al., which is incorporated byreference herein in its entirety, describes derivatives of radicicol,including cyclopropyl analogs, and the use of these compounds astherapeutic agents.

International Publication No. WO 2008/021213 to Winssinger et al., whichis incorporated by reference herein in its entirety, describes certainanalogs and derivatives of radicicol and pochonins useful as inhibitorsof HSP90, including pharmaceutical compositions comprising the compoundsand methods for the treatment of various diseases mediated by HSP90.

International Publication No. WO 2008/150302 to NexgenixPharmaceuticals, which is incorporated by reference herein in itsentirety, describes uses and methods for the treatment ofneurofibromatosis with analogs and derivatives of radicicol andpochonins.

Despite the progress described above, chemical biologists continue tosuffer from a limited ability to knock out specific kinase activity inorder to deconvolute the role of specific kinases within complexsignaling networks. Small molecules that can permeate cells have promisefor solving this problem. And it has become increasingly apparent thatthe biological function of kinases is often regulated by theirconformation, which is in turn dictated by their phosphorylation leveland by intra- and inter-molecular associations. Small moleculeinhibitors also have the potential to discriminate between differentconformations of a given kinase, thus small molecules offer a means todissect the respective functions of those conformation. Unfortunatelythe portfolio of known kinase inhibitors cannot yet support the fullrange of work to be done in parsing the roles of the various members ofthe kinome. This is not a merely academic pursuit, because therationality of drug design will continue to suffer until kinasemechanisms and their selectivity is understood.

Thus there is an ongoing need for kinase inhibitors and HSP90 inhibitorsthat have improved potency and selectivity. Moreover, the design andsynthesis of such inhibitors and of targeted libraries of inhibitorsremains challenging, thus there is an ongoing need for improvedsynthetic methods.

SUMMARY OF THE INVENTION

Novel analogs of the pochonin macrolides of formulae I, I′, II, II′,III, III′, IV and V, tautomers thereof, pharmaceutically acceptablesalts, solvates, esters or prodrugs thereof, and pharmaceuticalcompositions comprising the compounds for the treatment ofkinase-mediated or HSP90-mediated disorders are provided. Also presentedare methods for the treatment of kinase-mediated or HSP90-mediateddisorders using the compounds. In another embodiment, the inventionprovides the use of the compounds of formulae I, I′, II, II′, III, III′,IV and V, in the treatment of a kinase-mediated or HSP90-mediateddisorder or in the manufacture of a medicament for the treatment of akinase-mediated or HSP90-mediated disorder in a patient. The compoundsof the invention are active as kinase inhibitors and inhibitors ofHSP90. In addition, improved processes for the preparation of thecompounds are provided.

In one embodiment, the invention provides a compound of formula I or I′,or a tautomer thereof, or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof:

wherein:

X is O, S or NR;

Y is —OR, —O—(CH₂)_(m)COOR, —O—(CH₂)_(m)CON(R)₂, —N(R)₂, —N(R)SOR or—N(R)SO₂R, wherein the groups bound to the nitrogen atom may be in Z- orE-configuration;

R¹ and R² are independently hydrogen, halogen, OR, N(R)₂, SR, azido,nitro, cyano, aliphatic, aryl, alkylaryl, arylalkyl, heterocyclyl,heteroaryl, —S(O)R, —S(O)₂R, —SO₂N(R)₂, —N(R)SO₂R, —N(CO)R, —N(CO)N(R)₂,—N(CO)OR, —O(CO)R, —(CO)R, —(CO)OR, —(CO)N(R)₂, —O(CO)OR, or—O(CO)N(R)₂;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, halogen,azido, nitro, cyano, aliphatic, alkylaryl, aralkyl, aryl, heteroalkyl,alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R; and

each R is independently R¹¹, hydrogen, aliphatic, amino, azido, cyano,nitro, alkylamino, dialkylamino, OH, alkoxy, carbonylamino,aminocarbonyl, alkoxycarbonyl, carbonyloxy, carboxy, acyl, aryl,alkaryl, arylalkyl including benzyl, heteroalkyl, heteroaryl,heterocyclyl, or a protecting group; or two R on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclic orheteroaryl ring; wherein where a group contains more than one Rsubstituent; wherein R is optionally substituted, and each R can be thesame or different;

R¹¹ is the group:

where Z is an inorganic or organic counterion;

n is 0, 1 or 2;

m and p are independently 0, 1, 2, 3, 4 or 5; and the dashed linesindicate either a single or a double bond, where the valencerequirements are fulfilled by additional hydrogen atoms;

wherein in formula I′, when n is 1, and X is O and a double bond ispresent between the carbon atoms bearing R⁹ and R¹⁰, then at least oneof R⁵, R⁶, R⁷, R⁸, R⁹ or R¹⁰ is not hydrogen; and

wherein in formula I′, when n is 1 and X is O and the bond between thecarbon atoms bearing R⁹ and R¹⁰ is a single bond, then at least one ofR⁵, R⁶, R⁷ or R⁸ is not hydrogen.

In one embodiment of formulae I or I′, R¹ and R² are independentlyhydrogen or halogen. In another embodiment of formulae I or I′, X is Oor NR. In still another embodiment of formulae I or I′, X is O, S or NR;Y is —OR, —O—(CH₂)_(m)COOR, —O—(CH₂)_(m)CON(R)₂,

In another embodiment, a compound of formula II or II′, or a tautomer,pharmaceutically acceptable salt, solvate, ester or prodrug thereof, isprovided:

where the variables X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R, mand p are as defined for formula I; and wherein in formula II′, when Xis O, then at least one of R⁵, R⁶, R⁷, R⁸, R⁹ or R¹⁰ is not hydrogen.

In one embodiment of formulae II or II′, R¹ and R² are independentlyhydrogen or halogen. In another embodiment, R³ and are R⁴ areindependently alkyl or hydrogen. In still another embodiment of formulaeII or II′, variables R⁹ and R¹⁰ are independently hydrogen or aliphatic.

In another embodiment of formulae II or II′, X is O; Y is—O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups bound to thenitrogen atom may be in the Z- or E-configuration; R¹, R² areindependently hydrogen or halogen; and R⁹ and R¹⁰ are independentlyhydrogen or aliphatic.

In another embodiment, the invention provides a compound of formulae IIIor III′, or a tautomer, pharmaceutically acceptable salt, solvate, esteror prodrug thereof:

where the variables X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R, mand p are as defined for formula I, and wherein in formula III′, when Xis O, then at least one of R⁵, R⁶, R⁷ or R⁸ is not hydrogen.

In one embodiment of formulae III or III′, X is O or NR. In anotherembodiment, Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein thegroups bound to the nitrogen atom may be in the Z- or E-configuration.In still another embodiment of formulae III or III′, X is O, Y is—O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups bound to thenitrogen atom may be in the Z- or E-configuration; R¹ and R² areindependently hydrogen or halogen; and R⁹ and R¹⁰ are hydrogen.

In another aspect, the invention provides a compound of formula IV, or atautomer thereof, or a pharmaceutically acceptable salt, solvate, esteror prodrug thereof:

where the variables X, Y, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R, m andp are as defined for formula I above, and the dashed lines represents asingle or double bond.

In yet another aspect, the invention provides a compound of formula V,or a tautomer thereof, or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof:

where the variables X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R, mand p are as defined for formula I; R^(4a) has the same definition as R⁴in formula I above; and the dashed lines represents a single or doublebond.

In various other embodiments, the invention provides the macrocycliccompounds shown in Table 1 below, or tautomers thereof, orpharmaceutically acceptable salts, solvates, esters or prodrugs thereof.

Pharmaceutical compositions comprising an effective HSP 90-inhibitingamount of a compound of formulae I, I′, II, II′, III, III′, IV or V, incombination with a pharmaceutically acceptable carrier are provided forthe treatment of a disorder mediated by HSP 90. Also provided arepharmaceutical composition comprising an effective kinase-inhibitingamount of a compound of the invention, in combination with apharmaceutically acceptable carrier. In some embodiments, thepharmaceutical compositions comprise particles that are less than about2 microns average particle size. In other embodiments, the inventionprovides pharmaceutical compositions wherein the carrier is suitable fororal, parenteral, intravenous, inhalation, topical, or intradermaladministration. In addition, pharmaceutical compositions comprising thecompounds of the invention in combination with other active agents andpharmaceutically acceptable carriers are provided.

In another aspect of the invention, a method of treating a patient witha disease comprising administering to the patient an effective amount ofa compound of formulae I, I′, II, II′, III, III′, IV or V is provided,wherein the disease may be an autoimmune disease, an inflammatorydisease, a neurological or neurodegenerative disease, cancer, acardiovascular disease, an allergy, asthma, or a hormone-relateddisease. In one embodiment, the patient is a human patient. In anotherembodiment, use of the compounds in the manufacture of a medicament forthe treatment of the diseases is provided.

In one embodiment, the disease to be treated is cancer. The cancers thatmay be treated with the compounds include, but are not limited to, asolid tumor, blood borne tumor, breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, stomach, skin,keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, smallcell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas,adenocarcinoma, thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladdercarcinoma, liver carcinoma and biliary passages, kidney carcinoma,myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccalcavity, pharynx, lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,or leukemia.

In another embodiment, the method provided is for treating aninflammatory disease with the compounds of the invention. In variousembodiments, the inflammatory disease may be excessive or abnormalstimulation of endothelial cells, atherosclerosis, vascularmalfunctions, abnormal wound healing, inflammatory and immune disorders,Bechet's disease, gout or gouty arthritis, abnormal angiogenesisaccompanying rheumatoid arthritis, skin diseases, psoriasis, diabeticretinopathy, retinopathy of prematurity, retrolental fibroplasia,macular degeneration, corneal graft rejection, neovascular glaucoma orOsler Weber syndrome.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the tumor volume and animal weight change followingtreatment with compound 13a or control vehicle. Each point representsthe mean of measurements from 5 (for vehicle) or 6 (for 13a) animals.The experiment was carried out for 28 days and tumor volumes weredetermined weekly by caliper measurement. Student's t-test was used todetermine the statistical analysis of the difference between tumorvolumes of vehicle-treated and drug-treated animals. Individual bodyweights were also determined weekly. Statistical significance wasachieved (comparing tumor volumes in vehicle-treated and drug-treatedanimals) at day 21 for the q4d schedule (p=0.0497). In comparison, onthe q2d schedule increasing statistical significance was achieved ondays 14, 21, and 28, when comparing tumor volume of vehicle-treated anddrug-treated animals (p=0.012, p=0.007, and p=0.0002, respectively).

FIG. 2 shows the tumor histology in animals treated with compound 13aand animals treated with control vehicle. Top panels representhematoxylin & eosin (H & E) stained paraffin sections. Nuclei appearblue in color. The dark blue condensed nuclei in drug-treated tumors(right) are consistent with apoptotic cells. A dramatic loss ofcellularity in drug-treated tumors can also be clearly seen. Bottompanels represent TUNEL (terminal deoxynucleotidyl transferase-mediateddUTP-biotin nick end labeling)-stained paraffin sections. The highpreponderance of reddish-pink nuclei (positive for TUNEL staining) inthe drug-treated tumors reflects DNA fragmentation which ischaracteristic of apoptosis. Blue arrowheads point to characteristicTUNEL positive nuclei.

FIG. 3 shows a Wire-frame representation of the crystal structure ofcompound 13a.

FIG. 4 shows a Wire-frame representation of the crystal structure ofcompound 13b.

FIG. 5 shows a Wire-frame representation of the crystal structure of theZ-isomer of compound 13c.

DETAILED DESCRIPTION OF THE INVENTION

Provided are novel compounds based on the resorcylic acid lactones thatare useful as inhibitors of kinases and HSP90. Also provided arecompositions comprising the compounds and processes for the preparationof the compounds. Use of the compounds for the inhibition of kinases andHSP-90, and a method for the treatment of kinase-mediated orHSP90-mediated diseases comprising administering an effectivekinase-inhibiting amount or an effective HSP90-inhibiting amount of acompound of formula I, I′, II, II′, III, III′, IV or V to a patient witha kinase-mediated or HSP90-mediated disease, are provided.

Compounds

In a first embodiment of the invention, a compound of formula I, atautomer thereof, or a pharmaceutically acceptable salt, solvate, esteror prodrug thereof, is provided:

wherein:

X is O, S or NR;

Y is —OR, —O—(CH₂)_(m)COOR, —O—(CH₂)_(m)CON(R)₂, —N(R)₂, —N(R)SOR or—N(R)SO₂R, wherein the groups bound to the nitrogen atom may be in Z- orE-configuration;

R¹ and R² are independently hydrogen, halogen, OR, N(R)₂, SR, azido,nitro, cyano, aliphatic, aryl, alkylaryl, arylalkyl, heterocyclyl,heteroaryl, —S(O)R, —S(O)₂R, —SO₂N(R)₂, —N(R)SO₂R, —N(CO)R, —N(CO)N(R)₂,—N(CO)OR, —O(CO)R, —(CO)R, —(CO)OR, —(CO)N(R)₂, —O(CO)OR, or—O(CO)N(R)₂;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, halogen,azido, nitro, cyano, aliphatic, alkylaryl, aralkyl, aryl, heteroalkyl,alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R; and

each R is independently R¹¹, hydrogen, aliphatic, amino, azido, cyano,nitro, alkylamino, dialkylamino, OH, alkoxy, carbonylamino,aminocarbonyl, alkoxycarbonyl, carbonyloxy, carboxy, acyl, aryl,alkaryl, arylalkyl including benzyl, heteroalkyl, heteroaryl,heterocyclyl, or a protecting group; or two R on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered, optionallysubstituted heterocyclic or heteroaryl ring; wherein R is optionallysubstituted, and each R can be the same or different;

R¹¹ is the group:

where Z is an inorganic or organic counterion;

n is 0, 1 or 2;

m and p are independently 0, 1, 2, 3, 4 or 5; and the dashed linesindicate either a single or a double bond, where the valencerequirements are fulfilled by additional hydrogen atoms.

In a second embodiment, a compound of formula I′, a tautomer thereof, ora pharmaceutically acceptable salt, solvate, ester or prodrug thereof,is provided,

wherein X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R, n, m and p areas defined for formula I above and the dashed lines represent a singleor double bond, with the provisos that when n is 1, and X is O and adouble bond is present between the carbon atoms bearing R⁹ and R¹⁰, thenat least one of R⁵, R⁶, R⁷, R⁸, R⁹ or R¹⁰ is not hydrogen; and when n is1 and X is O and the bond between the carbon atoms bearing R⁹ and R¹⁰ isa single bond, then at least one of R⁵, R⁶, R⁷ or R⁸ is not hydrogen.

In one embodiment of formula I or I′, n is 0. In another embodiment offormula I or I′, n is 1. In still another embodiment of formula I or I′,n is 2.

In another embodiment of formula I or I′, X is O or NR and n is 1. Inanother embodiment of formula I or I′, X is O or NR, n is 1 and a doublebond is present between the carbon atoms bearing R⁹ and R¹⁰.

In yet another embodiment of formula I or I′, X is O or NR, n is 1 andthe bond between the carbon atoms bearing R⁹ and R¹⁰ is a single bond.

In another embodiment of formula I or I′, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration.

In another embodiment of formula I or I′, R¹ and R² are hydrogen.

In still another embodiment of formula I or I′, R³ and R⁴ areindependently alkyl or hydrogen.

In still another embodiment of formula I or I′, X is O, and R⁹ and R¹⁰are hydrogen.

In another embodiment of formula I or I′, X is O, Y is —O—(CH₂)_(m)COORor —O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atommay be in the Z- or E-configuration; R¹ and R² are independentlyhydrogen or halogen; and R⁹ and R¹⁰ are hydrogen.

In another embodiment of formula I or I′, R⁷ or R⁸ are not hydrogen oraliphatic.

In another embodiment of formula I or I′, R³ or R⁴ are not hydrogen oraliphatic.

In one embodiment of formula I or I′, the invention provides a compoundwherein:

X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen, OR, N(R)₂ or aliphatic;

R³ and R⁴ are independently hydrogen, aliphatic, OR, N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁷ and R⁸ are independently hydrogen, halogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)OC(O)(CH₂)_(p)OR,—NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N(R)C(O)CH₂)_(p)R,—(CH₂)_(m)OC(O)(CH₂)_(p)R, —(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)OC(O)(CH₂)_(p)OR,—(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R.

In yet another embodiment of formula I or I′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³ and R⁴ are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl; and

R⁷ and R⁸ are independently hydrogen, aliphatic, alkylaryl, aralkyl,aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂,SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In still another embodiment of formula I or I′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³ and R⁴ are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl;

R⁷ and R⁸ are independently alkylaryl, aralkyl, aryl, heteroalkyl,alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In one embodiment of formula I or I′, R is R¹¹, where the counterion Zis a halogen, acetate, formate, sulfonate, sulfate or phosphatecounterion.

In another embodiment, a compound of formula II, a tautomer thereof, ora pharmaceutically acceptable salt, solvate, ester or prodrug thereof,is provided:

wherein the variables X, Y, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R, mand p are as defined for formula I above.

In another embodiment, a compound of formula II′, a tautomer thereof, ora pharmaceutically acceptable salt, solvate, ester or prodrug thereof,is provided:

wherein the variables X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R,m and p are as defined for formula I above; with the proviso that when Xis O, then at least one of R⁵, R⁶, R⁷, R⁸, R⁹ or R¹⁰ is not hydrogen.

In one embodiment of formula II or II′, X is O or NR.

In another embodiment of formula II or II′, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration.

In another embodiment of formula II or II′, R¹ and R² are hydrogen.

In still another embodiment of formula II or II′, R³ and R⁴ areindependently alkyl or hydrogen.

In still another embodiment of formula II or II′, X is O, and R⁹ and R¹⁰are hydrogen.

In another embodiment of formula II or II′, R⁷ or R⁸ are not hydrogen oraliphatic.

In another embodiment of formula II or II′, R³ or R⁴ are not hydrogen oraliphatic.

In another embodiment of formula II or II′, X is O, Y is—O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups bound to thenitrogen atom may be in the Z- or E-configuration; R¹ and R² areindependently hydrogen or halogen; and R⁹ and R¹⁰ are hydrogen.

In one embodiment of formula II or II′, the invention provides acompound wherein:

X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen, OR, N(R)₂ or aliphatic;

R³ and R⁴ are independently hydrogen, aliphatic, OR, N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R; and

R⁷ and R⁸ are independently hydrogen, halogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)OC(O)(CH₂)_(p)OR,—NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N(R)C(O)CH₂)_(p)R,—(CH₂)_(m)OC(O)(CH₂)_(p)R, —(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)OC(O)(CH₂)_(p)OR,—(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R.

In yet another embodiment of formula II or II′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen or halogen;

R³ and R⁴ are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl; and

R⁷ and R⁸ are independently hydrogen, aliphatic, alkylaryl, aralkyl,aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂,SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In still another embodiment of formula II or II′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen or halogen;

R³ and R⁴ are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl;

R⁷ and R⁸ are independently alkylaryl, aralkyl, aryl, heteroalkyl,alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In yet another embodiment of formula II or II′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen or halogen;

R³ and R⁴ are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl; and

R⁷ and R⁸ are independently —OR, —N(R)₂, —SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In another embodiment, a compound of formula III, a tautomer thereof, ora pharmaceutically acceptable salt, solvate, ester or prodrug thereof,is provided:

wherein the variables X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R,m and p are as defined for formula I above.

In another embodiment of the invention, a compound of formula III′, atautomer thereof, or a pharmaceutically acceptable salt, solvate, esteror prodrug thereof, is provided:

wherein the variables X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R,m and p are as defined for formula I above; with the proviso that atleast one of R⁵, R⁶, R⁷ or R⁸ is not hydrogen.

In one embodiment of formula III or III′, X is O or NR.

In another embodiment of formula III or III′, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration.

In another embodiment of formula III or III′, R¹ and R² are hydrogen.

In still another embodiment of formula III or III′, R³ and R⁴ areindependently alkyl or hydrogen.

In still another embodiment of formula III or III′, X is O, and R⁹ andR¹⁰ are hydrogen.

In another embodiment of formula III or III′, R³ or R⁴ are not hydrogenor aliphatic.

In another embodiment of formula III or III′, R⁷ or R⁸ are not hydrogenor aliphatic.

In still another embodiment of formula III or III′, R⁹ or R¹⁰ areindependently OR, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)OR,—NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In another embodiment of formula III or III′, X is O, Y is—O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups bound to thenitrogen atom may be in the Z- or E-configuration; R¹ and R² areindependently hydrogen or halogen; and R⁹ and R¹⁰ are hydrogen.

In one embodiment of formula III or III′, the invention provides acompound wherein:

X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen, OR, N(R)₂ or aliphatic;

R³ and R⁴ are independently hydrogen, aliphatic, OR, N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁵ and R⁶ are independently hydrogen, aliphatic, alkylaryl, aralkyl,aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, halogen, aliphatic,alkylaryl, aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl,heteroaryl, OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH_(2p)OR(CH₂R(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R; and R, m and p are as defined above forformula I.

In yet another embodiment of formula III or III′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³ and R⁴ are independently hydrogen, aliphatic, OR, N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵ and R⁶ are independently hydrogen, aliphatic, aralkyl, heteroalkyl,heterocyclyl, or heteroaryl; and

R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or—NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In yet another embodiment of formula III or III′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³ and R⁴ are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁷ and R⁶ are independently hydrogen, aliphatic, aralkyl, heteroalkyl,heterocyclyl, or heteroaryl;

R⁷, R⁸ are independently alkylaryl, aralkyl, aryl, heteroalkyl,alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂; and

R⁹ and R¹⁰ independently hydrogen, aliphatic, alkylaryl, aralkyl, aryl,heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In yet another embodiment of formula III or III′, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³ and R⁴ are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵ and R⁶ are independently hydrogen, aliphatic, aralkyl, heteroalkyl,heterocyclyl, or heteroaryl;

R⁷, R⁸ are independently OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or—NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂; and

R⁹ and R¹⁰ independently hydrogen, aliphatic, alkylaryl, aralkyl, aryl,heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In another embodiment of the invention, a compound of formula IV, atautomer thereof, or a pharmaceutically acceptable salt, solvate, esteror prodrug thereof, is provided:

wherein the variables X, Y, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R, mand p are as defined for formula I above; and the dashed linesrepresents a single or double bond.

In one embodiment of formula IV, X is O or NR.

In another embodiment of formula IV, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration.

In another embodiment of formula IV, R¹ and R² are hydrogen.

In still another embodiment of formula IV, R³ and R⁴ are independentlyalkyl or hydrogen.

In still another embodiment, X is O, and R⁹ and R¹⁰ are hydrogen.

In another embodiment of formula IV, R⁷ or R⁸ are not hydrogen oraliphatic.

In another embodiment of formula IV, R³ or R⁴ are not hydrogen oraliphatic.

In another embodiment of formula IV, X is O, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration; R¹ and R² are independently hydrogen orhalogen; and R⁹ and R¹⁰ are hydrogen.

In another embodiment of formula IV, X is O or NR, and a double bond ispresent between the carbon atoms bearing R⁹ and R¹⁰.

In yet another embodiment of formula IV, X is O or NR, and the bondbetween the carbon atoms bearing R⁹ and R¹⁰ is a single bond.

In another embodiment of formula IV, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration.

In one embodiment of formula IV, the invention provides a compoundwherein:

X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen, OR, N(R)₂ or aliphatic;

R³ is hydrogen, aliphatic, OR, N(R)₂, —(CH₂)_(m)N(R)C(O)CH₂)_(p)R,—(CH₂)_(m)OC(O)(CH₂)_(p)R, —(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)OC(O)(CH₂)_(p)OR,—(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R; and

R⁷ and R⁸ are independently hydrogen, halogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR(CH₂R(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R.

In yet another embodiment of formula IV, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³ is hydrogen, aliphatic, OR, N(R)₂, —(CH₂)_(m)N(R)C(O)CH₂)_(p)R,—(CH₂)_(m)OC(O)(CH₂)_(p)R, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)OC(O)(CH₂)_(p)OR,—(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃, —(CH₂)_(m)N(R)₂, or—(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl; and

R⁷ and R⁸ are independently hydrogen, aliphatic, alkylaryl, aralkyl,aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂,SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In yet another embodiment of formula IV, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³ is hydrogen, aliphatic, OR, N(R)₂, —(CH₂)_(m)N(R)C(O)CH₂)_(p)R,—(CH₂)_(m)OC(O)(CH₂)_(p)R, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)OC(O)(CH₂)_(p)OR,—(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃, —(CH₂)_(m)N(R)₂, or—(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl;

R⁷ and R⁸ are independently OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In another embodiment of the invention, a compound of formula V, atautomer thereof, or a pharmaceutically acceptable salt, solvate, esteror prodrug thereof, is provided,

wherein the variables X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R,m and p are as defined for formula I above; and R^(4a) is as defined forR⁴ in formula I above; and the dashed lines represents a single ordouble bond.

In one embodiment of formula V, X is O or NR. In another embodiment offormula V, X is O or NR, and a double bond is present between the carbonatoms bearing R⁹ and R¹⁰.

In yet another embodiment of formula V, X is O or NR, and the bondbetween the carbon atoms bearing R⁹ and R¹⁰ is a single bond.

In another embodiment of formula V, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration.

In another embodiment of formula V, R¹ and R² are hydrogen.

In still another embodiment of formula V, R³ is alkyl or hydrogen.

In still another embodiment of formula V, R⁴ and R^(4a) areindependently alkyl or hydrogen.

In still another embodiment of formula V, X is O, and R⁹ and R¹⁰ arehydrogen.

In another embodiment of formula V, X is O, Y is —O—(CH₂)_(m)COOR or—O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom maybe in the Z- or E-configuration; R¹ and R² are independently hydrogen orhalogen; and R⁹ and R¹⁰ are hydrogen.

In one embodiment of formula V, the invention provides a compoundwherein:

X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen, OR, N(R)₂ or aliphatic;

R³, R⁴ and R^(4a) are independently hydrogen, aliphatic, OR, N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R;

R⁷ and R⁸ are independently hydrogen, halogen, aliphatic, alkylaryl,aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl,OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR,—O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R,—NR(CH₂)_(m)OC(O)(CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)OC(O)(CH₂)_(p)OR,—NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N(R)C(O)CH₂)_(p)R,—(CH₂)_(m)OC(O)(CH₂)_(p)R, —(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)OC(O)(CH₂)_(p)OR,—(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R,—(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or—(CH₂)_(m)N(R)SO₂(CH₂)_(p)R.

In yet another embodiment of formula V, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³, R⁴ and R^(4a) are independently hydrogen, aliphatic, OR, N(R)₂,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl; and

R⁷ and R⁸ are independently hydrogen, aliphatic, alkylaryl, aralkyl,aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂,SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In yet another embodiment of formula V, X is O or NR;

Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups boundto the nitrogen atom may be in the Z- or E-configuration;

R¹ and R² are independently hydrogen, halogen;

R³, R⁴ and R^(4a) are independently hydrogen, aliphatic,—(CH₂)_(m)N(R)C(O)CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R,—(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR;

R⁵, R⁶, R⁹ and R¹⁰ are independently hydrogen, aliphatic, aralkyl,heteroalkyl, heterocyclyl, or heteroaryl;

R⁷ and R⁸ are independently OR, N(R)₂, SR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R,—O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR,—O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O)(CH₂)_(p)R,—NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR,—NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂,—NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, or —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂.

In specific embodiments of the present invention, the compoundspresented in Table 1, tautomers thereof, or pharmaceutically acceptablesalts, solvates, esters or prodrugs thereof, are provided:

TABLE 1

Pharmaceutically Acceptable Salts and Prodrugs

The terms “pharmaceutically acceptable salt” and “prodrug” are usedthroughout the specification to describe any pharmaceutically acceptableform (such as a salt, an ester, a phosphate ester, salt of an ester or arelated group) of a compound which, upon administration to a patient,provides the compound described in the specification. In cases wherecompounds are sufficiently basic or acidic to form stable nontoxic acidor base salts, administration of the compounds as salts may beappropriate. The term pharmaceutically acceptable salts or complexesrefers to salts or complexes that retain the desired biological activityof the compounds of the present invention and exhibit minimal undesiredtoxicological effects.

Non-limiting examples of such salts are (a) acid addition salts formedwith inorganic acids such as sulfate, nitrate, hydrochloric, phosphate,and the like. For example, salts formed by the addition of hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, andthe like. In addition, salts formed with organic acids are encompassedby the invention, including tosylate, methanesulfonate, acetate,citrate, malonate, tartrate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate salts, such as acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid,benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, naphthalenedisulfonic acid, andpolygalacturonic acid. The invention also encompasses (b) base additionsalts, including formed with metal cations such as zinc, calcium,bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium,sodium, potassium, lithium and the like, or with a cation formed fromammonia, N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium,or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinctannate salt or the like. Also included in this definition arepharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR⁺A⁻, wherein R is as defined above and A is a counterion,including chloride, bromide, iodide, —O-alkyl, toluenesulfonate,methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate,succinate, acetate, glycolate, maleate, malate, citrate, tartrate,ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, anddiphenylacetate.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion.

Pharmaceutically acceptable “prodrugs” refer to a compound that ismetabolized, for example hydrolyzed or oxidized, in the host to form thecompound of the present invention. Typical examples of prodrugs includecompounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound. For example, a suitable prodrug may be an ester or anamide of a carboxylic acid that is hydrolyzed to form the acid.Non-limiting examples of prodrugs include but are not limited to alkylor aralkyl esters or amides, including methyl, ethyl, propyl, benzyl andsubstituted benzyl esters or amides. Prodrugs also comprise phosphateesters of the compounds.

Stereoisomerism and Polymorphism

Compounds of the present invention having a chiral center may exist inand be isolated in optically active and racemic forms. The presentinvention encompasses any racemic, optically-active, diastereomeric,polymorphic, or stereoisomeric form, or mixtures thereof, of a compoundof the invention, which possess the useful properties described herein.

In one embodiment, the compounds are prepared in optically active formby asymmetric synthesis using the processes described herein orsynthetic transformations known to those skilled in the art.

Other methods to obtain optically active materials are known in the art,and include at least the following.

i) physical separation of crystals—a technique whereby macroscopiccrystals of the individual enantiomers are manually separated. Thistechnique can be used if crystals of the separate enantiomers exist,i.e., the material is a conglomerate, and the crystals are visuallydistinct;

ii) simultaneous crystallization—a technique whereby the individualenantiomers are separately crystallized from a solution of the racemate,possible only if the latter is a conglomerate in the solid state;

iii) enzymatic resolutions—a technique whereby partial or completeseparation of a racemate by virtue of differing rates of reaction forthe enantiomers with an enzyme;

iv) enzymatic asymmetric synthesis—a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenatiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) chemical asymmetric synthesis—a synthetic technique whereby thedesired enantiomer is synthesized from an achiral precursor underconditions that produce asymmetry (i.e., chirality) in the product,which may be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomer separations—a technique whereby a racemic compound isreacted with an enantiomerically pure reagent (the chiral auxiliary)that converts the individual enantiomers to diastereomers. The resultingdiastereomers are then separated by chromatography or crystallization byvirtue of their now more distinct structural differences and the chiralauxiliary later removed to obtain the desired enantiomer;

vii) first- and second-order asymmetric transformations—a techniquewhereby diastereomers from the racemate equilibrate to yieldpreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

viii) kinetic resolutions—this technique refers to the achievement ofpartial or complete resolution of a racemate (or of a further resolutionof a partially resolved compound) by virtue of unequal reaction rates ofthe enantiomers with a chiral, non-racemic reagent or catalyst underkinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors—a synthetictechnique whereby the desired enantiomer is obtained from non-chiralstarting materials and where the stereochemical integrity is not or isonly minimally compromised over the course of the synthesis;

x) chiral liquid chromatography—a technique whereby the enantiomers of aracemate are separated in a liquid mobile phase by virtue of theirdiffering interactions with a stationary phase. The stationary phase canbe made of chiral material or the mobile phase can contain an additionalchiral material to provoke the differing interactions;

xi) chiral gas chromatography—a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

xii) extraction with chiral solvents—a technique whereby the enantiomersare separated by virtue of preferential dissolution of one enantiomerinto a particular chiral solvent; or

xiii) transport across chiral membranes—a technique whereby a racemateis placed in contact with a thin membrane barrier. The barrier typicallyseparates two miscible fluids, one containing the racemate, and adriving force such as concentration or pressure differential causespreferential transport across the membrane barrier. Separation occurs asa result of the non-racemic chiral nature of the membrane which allowsonly one enantiomer of the racemate to pass through.

Definitions

Whenever a term in the specification is identified as a range (i.e. C₁₋₄alkyl), the range independently refers to each element of the range. Asa non-limiting example, C₁₋₄ alkyl means, independently, C₁, C₂, C₃ orC₄ alkyl. Similarly, when one or more substituents are referred to asbeing “independently selected from” a group, this means that eachsubstituent can be any element of that group, and any combination ofthese groups can be separated from the group. For example, if R¹ and R²can be independently selected from X, Y and Z, this separately includesthe groups R¹ is X and R² is X; R¹ is X and R² is Y; R¹ is X and R² isZ; R¹ is Y and R² is X; R¹ is Y and R² is Y; R¹ is Y and R² is Z; R¹ isZ and R² is X; R¹ is Z and R² is Y; and R¹ is Z and R² is Z.

The term “aliphatic” as used herein means straight-chain, branched orcyclic typically of C₁ to C₁₈, and in certain embodiment of C₁ to C₁₀ orof C₁ to C₆, hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic, including but not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Aliphatic groups can be optionally substituted with one ormore moieties, including but not limited to, alkyl, halo, haloalkyl,hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives,alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,thiol, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl,sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl,phosphoryl, phosphine, thioester, thioether, acid halide, anhydride,oxime, hydrozine, carbamate, phosphonic acid, phosphate, phosphonate, orany other viable functional group that does not inhibit thepharmacological activity of this compound, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference.

The term “alkyl” as used herein, unless otherwise specified, refers to asaturated straight, branched, or cyclic, primary, secondary, or tertiaryhydrocarbon, including but not limited to groups typically of C₁ to C₁₈and in certain embodiment of C₁ to C₁₀ or of C₁ to C₆, and specificallyincludes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl, cyclopentyl, isopentyl, neopentyl, hexylisohexyl, cyclohexyl,cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and2,3-dimethylbutyl. Alkyl groups may be substituted as noted above forthe term “aliphatic.”

The term “lower alkyl,” as used herein, and unless otherwise specified,refers to optionally substituted C₁ to C₄ saturated straight, branched,or if appropriate, a cyclic (for example, cyclopropyl) alkyl group,including both substituted and unsubstituted forms.

Illustrative examples of alkyl groups are methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, secbutyl, isobutyl, tertbutyl,cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl,isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl.Unless otherwise specified, the alkyl group can be unsubstituted orsubstituted with one or more moieties selected from the group consistingof alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino,amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino,alkoxy, aryloxy, nitro, cyano, thiol, imine, sulfonic acid, sulfate,sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide,phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether,acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid,phosphate, phosphonate, or any other viable functional group that doesnot inhibit the pharmacological activity of this compound, eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in Greene et al., Protective Groups inOrganic Synthesis, John Wiley & Sons, 3^(rd) Ed., 1999.

The term “halo” or “halogen”, as used herein, includes chloro, bromo,iodo, and fluoro.

The term “chiral” as used herein includes a compound that has theproperty that it is not superimposable on its mirror image.

The term “tautomer” as used herein refers to alternate structures whichare recognized in the art to be in equilibrium with the depictedstructure. For example, the enol structure below is a tautomer of theketone structure and recognized to be in equilibrium with the ketonestructure.

As used herein, the term “solvate” or “pharmaceutically acceptablesolvate,” is a solvate formed from the association of one or moresolvent molecules to one or more molecules of a compound of any one offormulas I, I′, II, II′, III, III′, IV or V or the compounds depicted inTable 1. The term solvate includes hydrates (e.g., hemi-hydrate,mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

The term “alkylthio” refers to a straight or branched chain alkylsulfideof the number of carbons specified, such as for example, C₁₋₄alkylthio,ethylthio, —S-alkyl, —S— alkenyl, —S-alkynyl, etc.

The terms “alkylamino” or “arylamino” refer to an amino group that hasone or two alkyl or aryl substituents, respectively. Unless otherwisespecifically stated in this application, when alkyl is a suitablemoiety, then it is a lower alkyl, whether substituted or unsubstituted.

The term “alkylsulfonyl” means a straight or branched alkylsulfone ofthe number of carbon atoms specified, as for example, C₁₋₆alkylsulfonylor methylsulfonyl.

The term “alkoxycarbonyl” refers to a straight or branched chain esterof a carboxylic acid derivative of the number of carbon atoms specified,such as for example, a methoxycarbonyl, MeOCO—.

As used herein, the term “nitro” means —NO₂; the term “sulfhydryl” means—SH; and the term “sulfonyl” means —SO₂.

The terms “alkenyl” and “alkynyl” refer to alkyl moieties, includingboth substituted and unsubstituted forms wherein at least one saturatedC—C bond is replaced by a double or triple bond. Thus, C₂₋₆alkenyl maybe vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl. Similarly, C₂₋₆alkynylmay be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, or 5-hexynyl.

The term “alkylene” includes a saturated, straight chain, divalent alkylradical of the formula —(CH₂)_(n)—, wherein “n” may be any whole integerfrom 1 to 12.

“Alkyl”, “alkoxy”, “alkenyl”, “alkynyl”, etc., includes both straightchain and branched groups. However, reference to an individual radicalsuch as “propyl” embraces only that straight-chain radical, whereas abranched chain isomer such as “isopropyl” is specifically termed such.

The term “aryl” as used herein and unless otherwise specified refers toany stable monocyclic, bicyclic, or tricyclic carbon ring of up to 8members in each ring, wherein at least one ring is aromatic as definedby the Huckel 4n+2 rule, and especially phenyl, biphenyl, or naphthyl.The term includes both substituted and unsubstituted moieties. The arylgroup can be optionally substituted with one or more moieties. Examplesof substituents include alkyl, halo, haloalkyl, hydroxyl, carboxyl,acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino,dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,thiol, imine, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester,carboxylic acid, amide, phosphate, phosphonyl, phosphinyl, phosphoryl,phosphine, thioester, thioether, acid halide, anhydride, oxime,hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected,or protected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., “Protective Groups in OrganicSynthesis,” John Wiley and Sons, Second Edition, 1991.

The term “alkaryl” or “alkylaryl” refers to an alkyl group with an arylsubstituent or an alkyl group linked to the molecule through an arylgroup as defined herein. The term “aralkyl” or “arylalkyl” refers to anaryl group substituted with an alkyl substituent or linked to themolecule through an alkyl group as defined above.

The term “alkoxy” means a straight or branched chain alkyl group havingan attached oxygen radical, the alkyl group having the number of carbonsspecified or any number within this range. For example, a “—O-alkyl”,C₁₋₄ alkoxy, methoxy, etc.

The term “acyl” includes a group of the formula C(O)R′, wherein R′ is anstraight, branched, or cyclic alkyl (including lower alkyl), carboxylateresidue of an amino acid, aryl including phenyl, heteroaryl, alkaryl,aralkyl including benzyl, alkoxyalkyl including methoxymethyl,aryloxyalkyl such as phenoxymethyl; or substituted alkyl (includinglower alkyl), aryl including phenyl optionally substituted with chloro,bromo, fluoro, iodo, C₁ to C₄ alkyl or C to C₄ alkoxy, sulfonate esterssuch as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono,di or triphosphate ester, trityl or monomethoxy-trityl, substitutedbenzyl, alkaryl, aralkyl including benzyl, alkoxyalkyl includingmethoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups optimallycomprise a phenyl group. In non-limiting embodiments, acyl groupsinclude acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl,cyclopropyl-carboxy, propionyl, butyryl, isobutyryl, hexanoyl,heptanoyloctanoyl, neo-heptanoyl, phenylacetyl,2-acetoxy-2-phenylacetyl, diphenylacetyl,α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl,2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl,2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl,chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl,bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl,chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl,tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl,7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl,7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoro-heptanoyl,7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl,7H-dodeca-fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl,nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl,methyl 3-amino-5-phenylthiophene-2-carboxyl,3,6-dichloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl,2-bromo-propionyl, omega-aminocaproyl, decanoyl, n-pentadecanoyl,stearyl, 3-cyclopentyl-propionyl, 1-benzene-carboxyl, O-acetylmandelyl,pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl,2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl,perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolylcarbonyl, perfluorocyclohexyl carboxyl, crotonyl,1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,1-pyrrolidinecarbonyl, 4-phenylbenzoyl.

The term “acylamino” includes a group having a structure of“—N(R′)—C(═O)—R′”, wherein each R′ is independently as defined above.

The term “ester” includes a group of the structure “—C(═O)—O—R′” or“—O—C(═O)—R′”, wherein R′ is an straight, branched, or cyclic alkyl(including lower alkyl), carboxylate residue of an amino acid, arylincluding phenyl, heteroaryl, alkaryl, aralkyl including benzyl,alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl;or substituted alkyl (including lower alkyl), aryl including phenyloptionally substituted with chloro, bromo, fluoro, iodo, C₁ to C₄ alkylor C₁ to C₄ alkoxy, sulfonate esters such as alkyl or aralkyl sulphonylincluding methanesulfonyl, the mono, di or triphosphate ester, trityl ormonomethoxy-trityl, substituted benzyl, alkaryl, aralkyl includingbenzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such asphenoxymethyl. Aryl groups optimally comprise a phenyl group.

The term “heteroatom” includes an atom other than carbon or hydrogen inthe structure of a heterocyclic compound, nonlimiting examples of whichare nitrogen, oxygen, sulfur, phosphorus or boron.

The term “carbonyl” or “includes a group of the structure “—C(═O)—X—R′”or “X—C(═O)—R′”, where X is O, S, or a bond, and each R is independentlyas defined above for “ester”.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinincludes non-aromatic ring systems having four to fourteen members,preferably five to ten, in which one or more ring carbons, preferablyone to four, are each replaced by a heteroatom. Examples of heterocyclicrings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydro-furanyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetra-hydropyranyl, [1,3]-dioxolanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetra-hydro-thiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ringgroups having five to fourteen members. Examples of heteroaryl ringsinclude 2-furanyl, 3-furanyl, 3-furazanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2-pyrazolyl,3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrirnidyl,5-pyrirnidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl,carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, andbenzoisoxazolyl. Also included within the scope of the term“heteroaryl”, as it is used herein, is a group in which a heteroatomicring is fused to one or more aromatic or nonaromatic rings where theradical or point of attachment is on the heteroaromatic ring. Examplesinclude tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

The term “amino” as used herein unless otherwise specified, includes amoiety represented by the structure “—N(R)₂”, and includes primary,secondary and tertiary amines optionally substituted by alkyl, aryl,heterocyclyl, and/or sulfonyl groups. Thus (R)₂ may represent twohydrogen atoms, two alkyl moieties, or one hydrogen and one alkylmoiety.

The term “amido” as used herein includes an amino-substituted carbonyl,while the term “amidino” means a group having the structure“—C(═NH)—NH₂”.

The term “counterion” refers to a negatively or positively charged ionicspecies that accompanies an oppositely charged ionic species in order tomaintain electric neutrality. Negatively charged counterions includeinorganic counterions and organic counterions, including but not limitedto, chloro, bromo, iodo, fluoro, phosphate, acetate, formate, sulfonate,trifluoroacetate acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Positively charged counterionsinclude, but are not limited to, alkali metal (e.g., sodium andpotassium), alkaline earth metal (e.g., magnesium), ammonium and N⁺(C₁₋₄alkyl)₄ counterions.

The term “quaternary amine” as used herein includes quaternary ammoniumsalts that have a positively charged nitrogen. They are formed by thereaction between a basic nitrogen in the compound of interest and anappropriate quaternizing agent such as, for example, methyliodide orbenzyliodide. Appropriate counterions accompanying a quaternary amineinclude acetate, trifluoroacetate, chloro, bromo and iodo ions.

The term “substituted” includes multiple degrees of substitution by oneor more named substituents such as, for example, halo, hydroxyl, thio,alkyl, alkenyl, alkynyl, nitro, cyano, azido, amino, carboxamido, etc.Where multiple substituent possibilities exist, the compound can besubstituted by one or more of the disclosed or claimed substituentgroups, independently from one another, and taken singly or in plural.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

The term “protecting group” as used herein refers to a group that may beattached to a reactive group, including heteroatoms such as oxygen ornitrogen, to prevent the reactive group from participating in areaction. Any protecting groups taught in for example, in Greene et al.,Protective Groups in Organic Synthesis, John Wiley & Sons, 3^(rd) Ed.,1999, may be used. Examples of suitable protecting groups include butare not limited to alkoxyalkyl groups such as ethoxymethyl andmethoxymethyl; silyl protecting groups, such tert-butyldimethyl silyl(TBS), phenyldimethylsilyl, trimethylsilyl (TMS),2-trimethylsilylethoxymethyl (SEM) and 2-trimethylsilylethyl; and benzyland substituted benzyl.

It should be understood that the various possible stereoisomers of thegroups mentioned above and herein are within the meaning of theindividual terms and examples, unless otherwise specified. As anillustrative example, “1-methyl-butyl” exists in both (R) and the (S)form, thus, both (R)-1-methyl-butyl and (S)-1-methyl-butyl is covered bythe term “1-methyl-butyl”, unless otherwise specified.

The term “patient” includes human and veterinary subjects.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a patient oralternatively, the quantity of compound that possesses a desiredactivity in vivo or in vitro. In the case of proliferative disorders, abeneficial clinical outcome includes reduction in the extent or severityof the symptoms associated with the disease or disorder and/or anincrease in the longevity and/or quality of life of the patient comparedwith the absence of the treatment. For example, for a subject withcancer, a “beneficial clinical outcome” includes a reduction in tumormass, a reduction in the rate of tumor growth, a reduction inmetastasis, a reduction in the severity of the symptoms associated withthe cancer and/or an increase in the longevity of the subject comparedwith the absence of the treatment. The precise amount of compoundadministered to a subject will depend on the type and severity of thedisease or condition and on the characteristics of the patient, such asgeneral health, age, sex, body weight and tolerance to drugs. It willalso depend on the degree, severity and type of proliferative disorder.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors.

The term “kinase-inhibiting amount” as used herein, refers to an amountof the compound that inhibits a kinase enzyme compared to a control astested by the methods described herein.

The term “HSP 90-inhibiting amount” as used herein, refers to an amountof the compound that inhibits HSP90 compared to a control as tested bythe methods described herein.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

The term “cancer” includes, but is not limited to, solid tumors andblood borne tumors and include, but is not limited to, the followingcancers: breast, ovary, cervix, prostate, testis, genitourinary tract,esophagus, larynx, glioblastoma, stomach, skin, keratoacanthoma, lung,epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lungadenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid,follicular carcinoma, undifferentiated carcinoma, papillary carcinoma,seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma andbiliary passages, kidney carcinoma, myeloid disorders, lymphoiddisorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral),lip, tongue, mouth, pharynx, small intestine, colon-rectum, largeintestine, rectum, brain and central nervous system, and leukemia. Theterm “cancer” includes primary cancer, cancers secondary to treatment,and metastatic cancers.

The term “pharmaceutically acceptable carrier” refers to a non-toxiccarrier, adjuvant, or vehicle that may be administered to a patient,together with a compound of this invention, and which does not destroythe pharmacological activity thereof.

The terms “GSK-3-mediated disease, or “GSK-3-mediated condition”, asused herein, mean any disease or other deleterious condition or state inwhich GSK-3 is known to play a role. Such diseases or conditionsinclude, without limitation, diabetes, Alzheimer's disease, Huntington'sDisease, Parkinson's Disease, AIDS-associated dementia, amyotrophiclateral sclerosis (AML), multiple sclerosis (MS), schizophrenia,cardiomycete hypertrophy, reperfusion/ischemia, and baldness.

The terms “CDK-2-mediated disease” or CDK-2-mediated condition”, as usedherein, mean any disease or other deleterious condition in which CDK-2is known to play a role. The terms “CDK-2-mediated disease” or“CDK-2-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with a CDK-2 inhibitor. Such conditionsinclude, without limitation, cancer, Alzheimer's disease, restenosis,angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes,psoriasis, atherosclerosis, alopecia, and autoimmune diseases such asrheumatoid arthritis, such as are described for example in Fischer, P.M. and Lane, D. P., Current Medicinal Chemistry, 7, 1213-1245 (2000);Mani, S., Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Opin.Invest. Drugs, 9, 1849 (2000); Fry, D. W. and Garrett, M. D., CurrentOpinion in Oncologic, Endocrine & Metabolic Investigational Drugs, 2,40-59 (2000).

The terms “ERK-mediated disease” or “ERK-mediated condition”, as usedherein mean any disease or other deleterious condition in which ERK mayplay a role. The terms “ERK-2-mediated disease” or “ERK-2-mediatedcondition” also mean those diseases or conditions that are alleviated bytreatment with a ERK-2 inhibitor. Such conditions include, withoutlimitation, cancer, stroke, diabetes, hepatomegaly, cardiovasculardisease including cardiomegaly, Alzheimer's disease, cystic fibrosis,viral disease, autoimmune diseases, atherosclerosis, restenosis,psoriasis, allergic disorders including asthma, inflammation,neurological disorders and hormone-related diseases. ERK-2 proteinkinase and its implication in various diseases has been described forexample in Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al.,1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek etal., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027;Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996;Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al.,1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al.,1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir.Cell Mol. Biol. 16, 589.

The terms “AKT-mediated disease” or “AKT-mediated condition”, as usedherein, mean any disease or other deleterious condition in which AKT isknown to play a role. The terms “AKT-mediated disease” or “AKT-mediatedcondition” also mean those diseases or conditions that are alleviated bytreatment with a AKT inhibitor. AKT-mediated diseases or conditionsinclude, but are not limited to, proliferative disorders, cancer, andneurodegenerative disorders. The association of AKT, also known asprotein kinase B, with various diseases has been described for examplein Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q. Y., et al, Oncogene, 192000; Kazuhiko, N., et al, The Journal of Neuroscience, 20 2000.

The terms “Src-mediated disease” or “Src-mediated condition”, as usedherein mean any disease or other deleterious condition in which Src isknown to play a role. The terms “Src-mediated disease” or “Src-mediatedcondition” also mean those diseases or conditions that are alleviated bytreatment with a Src inhibitor. Such conditions include, withoutlimitation, hypercalcemia, osteoporosis, osteoarthritis, cancer,symptomatic treatment of bone metastasis, and Paget's disease. Srcprotein kinase and its implication in various diseases has beendescribed for example in Soriano, Cell, 69, 551 (1992); Soriano et al.,Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104, 137 (1999);Boschelli, Drugs of the Future 2000, 25(7), 717, (2000); Talamonti, J.Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys. Res. 243, 503(1998); Rosen, J. Biol. Chem., 261, 13754 (1986); Bolen, Proc. Natl.Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998);Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416(1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); Staley, Cell GrowthDiff., 8, 269 (1997).

The terms “Lck-mediated disease” or “Lck-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichLck is known to play a role. The terms “Lck-mediated disease” or“Lck-mediated condition” also mean those diseases or conditions that arealleviated by treatment with an Lck inhibitor. Lck-mediated diseases orconditions include, but are not limited to, autoimmune diseases such astransplant rejection, allergies, rheumatoid arthritis, and leukemia. Theassociation of Lck with various diseases has been described for examplein Molina et al., Nature, 357, 161 (1992).

The terms “Abl-mediated disease” or “Abl-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichAbl is known to play a role. The terms “Abl-mediated disease” or“Abl-mediated condition” also mean those diseases or conditions that arealleviated by treatment with an Abl inhibitor. Abl-mediated diseases orconditions include, but are not limited to, leukemias, particularlychronic myeloid leukemia. The association of Abl with various diseaseshas been described for example in Druker, et al., N. Engl. J Med. 2001,344, 1038-1042.

The terms “cKit-mediated disease” or “cKit-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichcKit is known to play a role. The terms “cKit-mediated disease” or“cKit-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with an cKit inhibitor. cKit-mediateddiseases or conditions include, but are not limited to,mastocytosis/mast cell leukemia, gastrointestinal stromal tumor,sinonasal natural killer/T-cell lymphoma, seminoma/dysgerminoma, thyroidcarcinoma, small-cell lung carcinoma, malignant melanoma, adenoid cysticcarcinoma, ovarian carcinoma, acute myelogenious leukemia, anaplasticlarge-cell lymphoma, angiosarcoma, endometrial carcinoma, pediatricT-cell ALL/lymphoma, breast carcinoma and prostate carcinoma. Theassociation of cKit with various diseases has been described for examplein Heinrich, et al., J. Clinical Oncology 2002, 20, 1692-1703.

The terms “Flt3-mediated disease” or “Flt3-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichFlt3 is known to play a role. The terms “Flt3-mediated disease” or“Flt3-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with an Flt3 inhibitor. Flt3-mediateddiseases or conditions include, but are not limited to, acutemyelogenous leukemia, mixed lineage leukemia and acute lymphocyticleukemia. The association of Flt3 with various diseases has beendescribed for example in Sternberg and Licht, Curr. Opin Hematol. 2004,12, 7-13.

The terms “KDR-mediated disease” or “KDR-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichKDR is known to play a role. The terms “KDR-mediated disease” or“KDR-mediated condition” also mean those diseases or conditions that arealleviated by treatment with an KDR inhibitor. KDR-mediated diseases orconditions include, but are not limited to, carcinoma of the lung,breast, gastrointestinal tract, kidney, bladder, ovary and endometrium,intracranial tumors including glioblastoma multiforme, sporadiccapillary hemangioblastoma, hematological malignancies, including T celllymphoma, acute lymphoblastic leukemia, Burkitt's lymphoma andpromyelocytic leukemia, age-related macular degeneration, herpeticocular disease, rheumatoid arthritis, cerebral ischemia andendometriosis. The association of KDR with various diseases has beendescribed for example in Ferrara, Endocrine Reviews 2004, 25, 581-611.

The term “HSP90-mediated disease” or “HSP90-mediated condition” refersto a condition in which HSP90 is known to pay a role. The conditionsinclude but are not limited to inflammatory disorders, abnormal cellularproliferation, autoimmune disorders, ischemia, fibrogenetic disordersincluding but not limited to scleroderma, polymyositis, systemic lupus,rheumatoid arthritis, liver cirrhosis, keloid formation, interstitialnephritis, and pulmonary fibrosis. (Strehlow, WO 02/02123;PCT/US01/20578).

Method of Treatment

The compounds described herein, are particularly useful for thetreatment or prevention of a disorder mediated by kinases or mediated byHSP90. In one embodiment, the compounds described herein, are useful forthe treatment or prevention of a proliferative disorder, includingcancer metastasis. In another embodiment, the compounds describedherein, are useful for the treatment or prevention of an inflammatory orautoimmune disorder associated by kinases or HSP90.

An aspect of the invention relates to compounds and compositions thatare useful for treating cancer.

Another aspect of the invention relates to the treatment of thefollowing cancers: breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, stomach, skin,keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, smallcell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas,adenocarcinoma, thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladdercarcinoma, liver carcinoma and biliary passages, kidney carcinoma,myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,and leukemia.

Another aspect of the invention is a method for treating cancercomprising administering an effective amount of a compound of formula I,I′, II, II′, III, III′, IV or V described herein to a patient withcancer.

Angiogenesis is characterized by the proliferation of endothelial cellsto form new blood vessels (often called neovascularization). Inhibitionof mitosis of endothelial cells results in inhibition of angiogenesis.Another aspect of this invention therefore relates to inhibition ofundesirable mitosis, including undesirable angiogenesis. A mammaliandisease characterized by undesirable cell mitosis, as defined herein,includes, but is not limited to, excessive or abnormal stimulation ofendothelial cells (e.g., atherosclerosis), solid tumors and tumormetastasis, benign tumors, for example, hemangiomas, trachomas, andpyogenic granulomas, vascular malfunctions, abnormal wound healing,inflammatory and immune disorders, Bechet's disease, gout or goutyarthritis, abnormal angiogenesis accompanying rheumatoid arthritis, skindiseases, such as psoriasis, diabetic retinopathy and other ocularangiogenic diseases such as retinopathy of prematurity (retrolentalfibroplasic), macular degeneration, corneal graft rejection, neovascularglaucoma and Osler Weber syndrome (Osler-Weber-Rendu disease).

Other undesired angiogenesis involves normal processes includingovulation and implantation of a blastula. The compositions describedabove can be used as a birth control agent by reducing or preventinguterine vascularization required for embryo implantation. Accordingly,the compositions described above can be used to block ovulation andimplantation of a blastula or to block menstruation (induce amenorrhea).

Diseases associated with undesirable mitosis includingneovascularization can be treated according to the present invention.Such diseases include, but are not limited to, ocular neovasculardisease, diabetic retinopathy, retinopathy of prematurity, corneal graftrejection, neovascular glaucoma and retrolental fibroplasias, epidemickeratoconjunctivitis, Vitamin A deficiency, contact lens overwear,atopic keratitis, superior limbic keratitis, pterygium keratitis sicca,Sjögren's syndrome, acne rosacea, phylectenulosis, syphilis,Mycobacteria infections, lipid degeneration, chemical burns, bacterialulcers, fungal ulcers, Herpes simplex infections, Herpes zosterinfections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer,Terrien's marginal degeneration, marginal keratolysis, trauma,rheumatoid arthritis, systemic lupus, polyarteritis, Wegener'ssarcoidosis, Scleritis, Steven-Johnson disease, pemphigoid, radialkeratotomy, and corneal graph rejection.

Other diseases associated with undesirable mitosis includingneovascularization can be treated according to the present invention.Such diseases include, but are not limited to, sickle cell anemia,sarcoid, pseudoxanthoma elasticum, Paget's disease, vein occlusion,artery occlusion, carotid obstructive disease, chronic uveitis/vitritis,Lyme's disease, systemic lupus erythematosis, Eales' disease, Bechet'sdisease, infections causing a retinitis or choroiditis, presumed ocularhistoplasmosis, Best's disease, myopia, optic pits, Stargart's disease,pars planitis, chronic retinal detachment, hyperviscosity syndromes,toxoplasmosis, and post-laser complications. Other diseases include, butare not limited to, diseases associated with rubeosis(neovascularization of the iris and the angle) and diseases caused bythe abnormal proliferation of fibrovascular or fibrous tissue includingall forms of proliferative vitreoretinopathy, whether or not associatedwith diabetes.

Another aspect of the invention relates to the treatment of inflammatorydiseases including, but no limited to, excessive or abnormal stimulationof endothelial cells (e.g., atherosclerosis), solid tumors and tumormetastasis, benign tumors, for example, hemangiomas, acoustic neuromas,trachomas, and pyogenic granulomas, vascular malfunctions, abnormalwound healing, inflammatory and immune disorders, Bechet's disease, goutor gouty arthritis, abnormal angiogenesis accompanying rheumatoidarthritis, skin diseases, such as psoriasis, diabetic retinopathy andother ocular angiogenic diseases such as retinopathy of prematurity(retrolental fibroplasic), macular degeneration, corneal graftrejection, neovascular glaucoma and Osler Weber syndrome(Osler-Weber-Rendu disease). Other undesired angiogenesis involvesnormal processes including ovulation and implantation of a blastula.Accordingly, the compositions described above can be used to blockovulation and implantation of a blastula or to block menstruation(induce amenorrhea).

Another aspect of this invention relates to a method of inhibiting HSP90activity in a patient, comprising administering to a patient aneffective amount of a compound of formula I, I′, II, II′, III, III′, IVor V or a pharmaceutically acceptable salt or prodrug thereof. Theinvention also provides a method for treating a disease that is mediatedby HSP90.

Another aspect of this invention relates to a method of inhibitingAurora A activity in a patient, comprising administering to a patient aneffective amount of a compound of formula I, I′, II, II′, III, III′, IVor V or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprisingadministering to a patient an effective amount of a compound of formulaI, I′, II, II′, III, III′, IV or V or a pharmaceutically acceptable saltor prodrug thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I, I′, II,II′, III, III′, IV or V or a pharmaceutical composition thereof. Thismethod is especially useful for diabetic patients. Another methodrelates to inhibiting the production of hyperphosphorylated Tau protein,which is useful in halting or slowing the progression of Alzheimer'sdisease. Another method relates to inhibiting the phosphorylation ofβ-catenin, which is useful for treating schizophrenia.

Another aspect of the invention relates to inhibiting GSK-3 activity ina biological sample, which method comprises contacting the biologicalsample with a GSK-3 inhibitor of formula I, I′, II, II′, III, III′, IVor V.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient comprising administering to the patient a compoundof formula I, I′, II, II′, III, III′, IV or V or a compositioncomprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a CDK-2-mediated disease comprising administering to apatient in need of such a treatment a therapeutically effective amountof a compound of formula I, I′, II, II′, III, III′, IV or V or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting CDK-2 activity ina biological sample or a patient, which method comprises administeringto the patient a compound of formula I, I′, II, II′, III, III′, IV or V,or a composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing an ERK-2-mediated diseases comprising administering to apatient in need of such a treatment a therapeutically effective amountof a compound of formula I, I′, II, II′, III, III′, IV or V or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting ERK-2 activity ina biological sample or a patient, which method comprises administeringto the patient a compound of formula I, I′, II, II′, III, III′, IV or V,or a composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing an AKT-mediated diseases comprising administering to apatient in need of such a treatment a therapeutically effective amountof a compound of formula I, I′, II, II′, III, III′, IV or V or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting AKT activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I, I′, II, II′, III, III′, IV or V, ora composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a Src-mediated disease comprising administering to a patientin need of such a treatment a therapeutically effective amount of acompound of formula I, I′, II, II′, III, III′, IV or V or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I, I′, II, II′, III, III′, IV or V, ora composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing an Lck-mediated disease with an Lck inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I, I′, II,II′, III, III′, IV or V, or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Lck activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I, I′, II, II′, III, III′, IV or V, ora composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing an Abl-mediated disease with an Abl inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I, I′, II,II′, III, III′, IV or V, or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Abl activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I, I′, II, II′, III, III′, IV or V, ora composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a cKit-mediated disease comprising administering to a patientin need of such a treatment a therapeutically effective amount of acompound of formula I, I′, II, II′, III, III′, IV or V, or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting cKit activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I, I′, II, II′, III, III′, IV or V, ora composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a Flt3-mediated disease comprising administering to a patientin need of such a treatment a therapeutically effective amount of acompound of formula I, I′, II, II′, III, III′, IV or V, or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Flt3 activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I, I′, II, II′, III, III′, IV or V, ora composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a KDR-mediated disease comprising administering to a patientin need of such a treatment a therapeutically effective amount of acompound of formula I, I′, II, II′, III, III′, IV or V, or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting KDR activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I, I′, II, II′, III, III′, IV or V, ora composition comprising said compound.

An amount effective to inhibit protein kinase, is an amount that causesmeasurable inhibition of the kinase activity when compared to theactivity of the enzyme in the absence of an inhibitor. Any method may beused to determine inhibition, such as, for example, the BiologicalTesting Examples described below.

Pharmaceutical Compositions

Mammals, and specifically humans, suffering from a respiratory disordercan be treated by the inhalation, systemic, oral, topical, ortransdermal administration of a composition comprising an effectiveamount of the compounds described herein or a pharmaceuticallyacceptable salt, ester or prodrug thereof, optionally in apharmaceutically acceptable carrier or diluent.

The compounds or compositions are typically administered by oral orinhalation administration. Alternatively, compounds can be administeredsubcutaneously, intravenously, intraperitoneally, intramuscularly,parenterally, orally, submucosally, by inhalation, transdermally via aslow release patch, or topically, in an effective dosage range to treatthe target condition.

An effective dose can be readily determined by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining the effective dose, a number of factorsare considered including, but not limited to: the species of patient;its size, age, and general health; the specific disease involved; thedegree of involvement or the severity of the disease; the response ofthe individual patient; the particular compound administered; the modeof administration; the bioavailability characteristics of thepreparation administered; the dose regimen selected; and the use ofconcomitant medication.

In a separate embodiment, the compounds of the invention are in the formof an inhaled dosage. In this embodiment, the compounds may be in theform of an aerosol suspension, a dry powder or liquid particle form. Thecompounds may be prepared for delivery as a nasal spray or in aninhaler, such as a metered dose inhaler. Pressurized metered-doseinhalers (“MDI”) generally deliver aerosolized particles suspended inchlorofluorocarbon propellants such as CFC-11, CFC-12, or thenon-chlorofluorocarbons or alternate propellants such as thefluorocarbons, HFC-134A or HFC-227 with or without surfactants andsuitable bridging agents. Dry-powder inhalers can also be used, eitherbreath activated or delivered by air or gas pressure such as thedry-powder inhaler disclosed in the Schering Corporation InternationalPatent Application No. PCT/US92/05225, published 7 Jan. 1993 as well asthe Turbuhaler™ (available from Astra Pharmaceutical Products, Inc.) orthe Rotahaler™ (available from Allen & Hanburys) which may be used todeliver the aerosolized particles as a finely milled powder in largeaggregates either alone or in combination with some pharmaceuticallyacceptable carrier e.g. lactose; and nebulizers.

The compounds of the invention may be also administered in specific,measured amounts in the form of an aqueous suspension by use of a pumpspray bottle. The aqueous suspension compositions of the presentinvention may be prepared by admixing the compounds with water and otherpharmaceutically acceptable excipients. The aqueous suspensioncompositions according to the present invention may contain, inter alia,water, auxiliaries and/or one or more of the excipients, such as:suspending agents, e.g., microcrystalline cellulose, sodiumcarboxymethylcellulose, hydroxpropyl-methyl cellulose; humectants, e.g.glycerin and propylene glycol; acids, bases or buffer substances foradjusting the pH, e.g., citric acid, sodium citrate, phosphoric acid,sodium phosphate as well as mixtures of citrate and phosphate buffers;surfactants, e.g. Polysorbate 80; and antimicrobial preservatives, e.g.,benzalkonium chloride, phenylethyl alcohol and potassium sorbate.

Typical systemic dosages for all of the herein described conditions arethose ranging from 0.01 mg/kg to 1500 mg/kg of body weight per day as asingle daily dose or divided daily doses. Preferred dosages for thedescribed conditions range from 0.5-1500 mg per day. A more particularlypreferred dosage for the desired conditions ranges from 5-750 mg perday. Typical dosages can also range from 0.01 to 1500, 0.02 to 1000, 0.2to 500, 0.02 to 200, 0.05 to 100, 0.05 to 50, 0.075 to 50, 0.1 to 50,0.5 to 50, 1 to 50, 2 to 50, 5 to 50, 10 to 50, 25 to 50, 25 to 75, 25to 100, 100 to 150, or 150 or more mg/kg/day, as a single daily dose ordivided daily doses. In one embodiment, the compounds are given in dosesof between about 1 to about 5, about 5 to about 10, about 10 to about 25or about 25 to about 50 mg/kg. Typical dosages for topical applicationare those ranging from 0.001 to 100% by weight of the active compound.

The compounds are conveniently administered in units of any suitabledosage form, including but not limited to one containing from about 7 to3000 mg, from about 70 to 1400 mg, or from about 25 to 1000 mg of activeingredient per unit dosage form. For example, an oral dosage of fromabout 50 to 1000 mg is usually convenient, including in one or multipledosage forms of 50, 100, 200, 250, 300, 400, 500, 600, 700, 800, 900 or1000 mgs. Lower dosages may be preferable, for example, from about10-100 or 1-50 mgs. Also contemplated are doses of 0.1-50 mg, 0.1-20mgs., or 0.1-10 mgs. Furthermore, lower doses may be utilized in thecase of administration by a non-oral route, as for example, by injectionor inhalation.

The compound is administered for a sufficient time period to alleviatethe undesired symptoms and the clinical signs associated with thecondition being treated.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutic amount of compound in vivo in the absence of serious toxiceffects. Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions are generally known in the art. Theyinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,solvents, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, silicates, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes, oils,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Pharmaceutically accepted vehicles can contain mixtures ofmore than one excipient in which the components and the ratios can beselected to optimize desired characteristics of the formulationincluding but not limited to shelf-life, stability, drug load, site ofdelivery, dissolution rate, self-emulsification, control of release rateand site of release, and metabolism.

Formulations can be prepared by a variety of techniques known in theart. Examples of formulation techniques can be found in literaturepublications and in texts such as “Water-insoluble drug formulation”,edited by Rong Liu, 2000, Interpharm Press.

If administered intravenously, carriers can be physiological saline,bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) orphosphate buffered saline (PBS). Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or di-glycerides. Fatty acids, such as oleicacid and its glyceride derivatives are useful in the preparation ofinjectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions may also contain a long-chain alcoholdiluent or dispersant, such as carboxymethyl cellulose or similardispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms including emulsions andsuspensions. Other commonly used surfactants, such as Tweens, Spans andother surface-active emulsifying agents or bioavailability enhancerswhich are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Theactive ingredient may be administered at once, or may be divided into anumber of smaller doses to be administered at varying intervals of time.

One mode of administration of the active compound for systemic deliveryis oral. Oral compositions will generally include an inert diluent or anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theactive compound can be incorporated with excipients and used in the formof tablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar, shellac, or other enteric agents.

The compound or its salts can be administered as a component of anelixir, suspension, syrup, wafer, chewing gum or the like. A syrup maycontain, in addition to the active compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.

In a preferred embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) are also preferred as pharmaceuticallyacceptable carriers. These may be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811 (which is incorporated herein by reference in its entirety).For example, liposome formulations may be prepared by dissolvingappropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine,stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, andcholesterol) in an inorganic solvent that is then evaporated, leavingbehind a thin film of dried lipid on the surface of the container. Anaqueous solution of the compound is then introduced into the container.The container is then swirled by hand to free lipid material from thesides of the container and to disperse lipid aggregates, thereby formingthe liposomal suspension.

Suitable vehicles or carriers for topical application can be prepared byconventional techniques, such as lotions, suspensions, ointments,creams, gels, tinctures, sprays, powders, pastes, slow-releasetransdermal patches, suppositories for application to rectal, vaginal,nasal or oral mucosa. In addition to the other materials listed abovefor systemic administration, thickening agents, emollients, andstabilizers can be used to prepare topical compositions. Examples ofthickening agents include petrolatum, beeswax, xanthan gum, orpolyethylene, humectants such as sorbitol, emollients such as mineraloil, lanolin and its derivatives, or squalene.

Combination Treatment

The compound can also be mixed with other active materials which do notimpair the desired action, or with materials that supplement the desiredaction. The active compounds can be administered in conjunction, i.e.combination or alternation, with other medications used in the treatmentof disorders that are mediated by kinases or HSP90.

The compounds can be administered in combination or alternation withdrugs typically useful for treatment or prevention of asthma, such ascertain anti-inflammatory drugs and bronchodilators. Corticosteroids(inhaled and oral), mast cell stabilizers, and the leukotriene modifierdrugs are typically a useful anti-inflammatory medication for peoplesuffering from asthma. These drugs reduce swelling and mucus productionin the airways. Bronchodilators typically relieve the symptoms of asthmaby relaxing the muscle bands that tighten around the airways. Thisaction rapidly opens the airways, letting more air come in and out ofthe lungs. Bronchodilators also help clear mucus from the lungs.

Typically used compounds include Inhaled corticosteroids, which preventrather than relieve symptoms. Inhaled corticosteroids include: Advair (acombination medication that includes a corticosteroid (fluticasone) plusa long acting bronchodilator drug (in this case a β-2 adrenergicreceptor agonist, salmeterol)), aerobid (flunisolide), azmacort(triamcinolone), flovent (fluticasone), methylprednisolone, prednisone,pulmicort or serevent diskus (salmeterol powder), theophylline, qvar,and xopenex (levalbuterol), Inhaled corticosteroids come in three forms:the metered dose inhaler (MDI), dry powder inhaler (DPI) and nebulizersolutions. Systemic steroids include: methylprednisolone (Medrol,Methylpred, Solu-Medrol), prednisone (Deltasone) and prednisolone(Prelone, Pediapred, Orapred). Mast Cell Stabilizers include Intal andTilade, which work by preventing the release of irritating andinflammatory substances from mast cells. Leukotriene modifiers includeaccolate and singular and accolate (zafirlukast), singulair(montelukast) and zyflo (zileuton).

Other non-limiting examples of corticosteroids that can be used inalternation or combination therapy include but are not limited toglucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort(triamcinolone acetonide), Beclovet (Vanceril, beclomethasonedipropionate), Flovent (fluticasone), Pulmicort (budesonide),prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate,Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort,Betamethasone (Betamethasone Acetate, Betamethasone Benzoate,Betamethasone Dipropionate, Betamethasone Sodium Phosphate,Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide,Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate,Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, DeoxycortoneAcetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone,Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate,Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate,Dexamethasone Sodium Phosphate), Dichlorisone Acetate, DiflorasoneDiacetate, Diflucortolone Valerate, Difluprednate, Domoprednate,Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,Flumethasone (Flumethasone Pivalate), Flunisolide, FluocinoloneAcetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (FluocortoloneHexanoate, Fluocortolone Pivalate), Fluorometholone (FluorometholoneAcetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone,Fluticasone Propionate, Formocortal, Halcinonide, HalobetasolPropionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone(Hydrocortisone Acetate, Hydrocortisone Butyrate, HydrocortisoneCypionate, Hydrocortisone Hemisuccinate, Hydrocortisone SodiumPhosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate),Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate,Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate),Mometasone Furoate, Paramethasone Acetate, Prednicarbate, PrednisolamateHydrochloride, Prednisolone (Prednisolone Acetate, PrednisoloneHemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate,Prednisolone Sodium Succinate, Prednisolone Steaglate, PrednisoloneTebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide,Rimexolone, Suprarenal Cortex, Tixocortol Pivalate, Triamcinolone(Triamcinolone Acetonide, Triamcinolone Diacetate and TriamcinoloneHexacetonide).

When used to treat rheumatoid arthritis, the compounds of the presentinvention can be used in alternation or combination with any agent ordrug known for the treatment of rheumatoid arthritic, including but notlimited to: Remicade® (infliximab); methotrexate; Nonsteroidalanti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen;corticosteroid medications, such as Prednisone; Leflunomide; biologicagents such as etanercept, infliximab, adalimumab, and anakinra;celecoxib; tetracyclines; tumour necrosis factor (TNF) antagonists;nonsteroidal anti-inflammatories; cyclooxygenase-2 inhibitors;interleukin-1-receptor antagonist

Drugs in clinical investigation are contemplated, including but notlimited to: 681323 (p38 alpha kinase inhibitor) (GlaxoSmithKline);683699 (T-0047) (dual alpha 4 integrin antaginist) (GlaxoSmithKline);ABT-963 (Abbott Laboratories); AGIX-4207 (Atherogenics);alpha-L-iduronidase (Genzyme General), AMG719 (Amgen); AnergiX.RA(Corixa); anti-CD11 humanized MAb (Genentech); Arava (AventisPharmaceuticals); CDP 870 (Pfizer); CDP-870 (Pfizer); Celebrex (Pfizer);COX 189 (Novartis); eculizumab (Alexion Pharmaceuticals); HuMax-IL15(Amgen); IDEC 151 (IDEC Pharmaceuticals); IDEC-151/clenoliximab (IDECPharmaceuticals; IL-1 trap (Rengeneron Pharmaceuticals); interleukin-1(Regeneron Pharmaceuticals); interleukin-18 (Regeneron Pharmaceuticals);J695 (Abbott Laboratories); Oraprine (DORBioPharma); pegsunercept(soluble tumor necrosis factor-a receptor type 1)(Amgen); pralnacasan(Aventis); Prograf (Fujisawa Healthcare); r-IL-18 bp (Serono); R1487(kinase inhibitor)(Roche); Rituxan (Genentech); SB281832(GlaxoSmithKline); SCIO-323 (Scio); SCIO-469 (Scio) and Vitaxin(MedImmune).

In one embodiment, the compound of the present invention can also beadministered in combination or alternation with apazone, amitriptyline,chymopapain, collegenase, cyclobenzaprine, diazepam, fluoxetine,pyridoxine, ademetionine, diacerein, glucosamine, hylan (hyaluronate),misoprostol, paracetamol, superoxide dismutase mimics, TNFα receptorantagonists, TNFα antibodies, P38 Kinase inhibitors, tricyclicantidepressants, cJun kinase inhibitors or immunosuppressive agents, IVgamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate,FK-506, gold compounds such as Myochrysine (gold sodium thiomalate),platelet activating factor (PAF) antagonists such as thromboxaneinhibitors, leukotriene-D₄-receptor antagonists such as Accolate(zafirlukast), Ziflo (zileuton), leukotriene C₁, C₂ antagonists andinhibitors of leukotriene synthesis such as zileuton for the treatmentof arthritic disorders, inducible nitric oxide synthase inhibitors.

In another embodiment, the active compound is administered incombination or alternation with one or more other non-steroidalanti-inflammatory drug(s) (NSAIDS). Examples of NSAIDS that can be usedin alternation or combination therapy are carboxylic acids, propionicacids, fenamates, acetic acids, pyrazolones, oxicans, alkanones, goldcompounds and others that inhibit prostaglandin synthesis, preferably byselectively inhibiting cylcooxygenase-2 (COX-2). Some nonlimitingexamples of COX-2 inhibitors are Celebrex (celecoxib) and Vioxx(rofacoxib). Some non-limiting examples of NSAIDS are aspirin(acetylsalicylic acid), Dolobid (diflunisal), Disalcid (salsalate,salicylsalicylate), Trisilate (choline magnesium trisalicylate), sodiumsalicylate, Cuprimine (penicillamine), Tolectin (tolmetin), ibuprofen(Motrin, Advil, Nuprin Rufen), Naprosyn (naproxen, Anaprox, naproxensodium), Nalfon (fenoprofen), Orudis (ketoprofen), Ansaid(flurbiprofen), Daypro (oxaprozin), meclofenamate (meclofanamic acid,Meclomen), mefenamic acid, Indocin (indomethacin), Clinoril (sulindac),tolmetin, Voltaren (diclofenac), Lodine (etodolac), ketorolac,Butazolidin (phenylbutazone), Tandearil (oxyphenbutazone), piroxicam(Feldene), Relafen (nabumetone), Myochrysine (gold sodium thiomalate),Ridaura (auranofin), Solganal (aurothioglucose), acetaminophen,colchicine, Zyloprim (allopurinol), Benemid (probenecid), Anturane(sufinpyrizone), Plaquenil (hydroxychloroquine), Aceclofenac,Acemetacin, Acetanilide, Actarit, Alclofenac, Alminoprofen, Aloxiprin,Aluminium Aspirin, Amfenac Sodium, Amidopyrine, Aminopropylone, AmmoniumSalicylate, Ampiroxicam, Amyl Salicylate, Anirolac, Aspirin, Auranofin,Aurothioglucose, Aurotioprol, Azapropazone, Bendazac (Bendazac Lysine),Benorylate, Benoxaprofen, Benzpiperylone, Benzydamine hydrochloride,Bomyl Salicylate, Bromfenac Sodium, Bufexamac, Bumadizone Calcium,Butibufen Sodium, Capsaicin, Carbaspirin Calcium, Carprofen,Chlorthenoxazin, Choline Magnesium Trisalicylate, Choline Salicylate,Cinmetacin, Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol,Cymene, Diacerein, Diclofenac (Diclofenac Diethylammonium Salt,Diclofenac Potassium, Diclofenac Sodium), Diethylamine Salicylate,Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam,Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac,Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium,Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic,Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen,Glafenine, Glucametacin, Glycol Salicylate, Gold Keratinate,Harpagophytum Procumbens, Ibufenac, Ibuprofen, Ibuproxam, ImidazoleSalicylate, Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone,Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol, LithiumSalicylate, Lonazolac Calcium, Lomoxicam, Loxoprofen Sodium, LysineAspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid,Flufenamic Acid, Meloxicam, Methyl Butetisalicylate, Methyl Gentisate,Methyl Salicylate, Metiazinic Acid, Metifenazone, Mofebutazone,Mofezolac, Morazone Hydrochloride, Morniflumate, Morpholine Salicylate,Nabumetone, Naproxen (Naproxen Sodium), Nifenazone, Niflumic Acid,Nimesulide, Oxametacin, Oxaprozin, Oxindanac, Oxyphenbutazone,Parsalmide, Phenybutazone, Phenyramidol Hydrochloride, PicenadolHydrochloride, Picolamine Salicylate, Piketoprofen, Pirazolac,Piroxicam, Pirprofen, Pranoprofen, Pranosal, Proglumetacin Maleate,Proquazone, Protizinic Acid, Ramifenazone, Salacetamide, SalamidaceticAcid, Salicylamide, Salix, Salol, Salsalate, Sodium Aurothiomalate,Sodium Gentisate, Sodium Salicylate, Sodium Thiosalicylate, Sulindac,Superoxide Dismutase (Orgotein, Pegorgotein, Sudismase), Suprofen,Suxibuzone, Tenidap Sodium, Tenoxicam, Tetrydamine, Thurfyl Salicylate,Tiaprofenic, Tiaramide Hydrochloride, Tinoridine Hydrochloride,Tolfenamic Acid, Tometin Sodium, Triethanolamine Salicylate, Ufenamate,Zaltoprofen, Zidometacin and Zomepirac Sodium.

In one embodiment, the compound(s) of the present invention can beadministered in combination or alternation one or moreanti-proliferative agents. Any of the antiproliferative agents listedbelow, or any other such agent known or discovered to exhibit anantiproliferative effect can be used in combination or alternation withthe present invention to achieve a combination therapeutic effect.

Representative adjuncts include levamisole, gallium nitrate,granisetron, sargramostim strontium-89 chloride, filgrastim,pilocarpine, dexrazoxane, and ondansetron. Physicians' Desk Reference,50th Edition, 1996.

Representative androgen inhibitors include flutamide and leuprolideacetate. Physicians' Desk Reference, 50th Edition, 1996.

Representative antibiotic derivatives include doxorubicin, bleomycinsulfate, daunorubicin, dactinomycin, and idarubicin.

Representative antiestrogens include tamoxifen citrate and analogsthereof. Physicians' Desk Reference, 50th Edition, 1996. Additionalantiestrogens include nonsteroidal antiestrogens such as toremifene,droloxifene and roloxifene. Magarian et al., Current MedicinalChemistry, 1994, Vol. 1, No. 1.

Representative antimetabolites include fluorouracil, fludarabinephosphate, floxuridine, interferon alfa-2b recombinant, methotrexatesodium, plicamycin, mercaptopurine, and thioguanine. Physicians' DeskReference, 50th Edition, 1996.

Representative cytotoxic agents include doxorubicin, carmustine (BCNU),lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucinephosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine,mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin,cisplatin, interferon alfa-2a recombinant, paclitaxel, teniposide, andstreptozoci. Physicians' Desk Reference, 50th Edition, 1996.

Representative hormones include medroxyprogesterone acetate, estradiol,megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate,testolactone, and goserelin acetate. Physicians' Desk Reference, 50thEdition, 1996.

Representative immunodilators include aldesleukin. Physicians' DeskReference, 50th Edition, 1996.

Representative nitrogen mustard derivatives include melphalan,chlorambucil, mechlorethamine, and thiotepa. Physicians' Desk Reference,50th Edition, 1996.

Representative steroids include betamethasone sodium phosphate andbetamethasone acetate. Physicians' Desk Reference, 50th Edition, 1996.

Representative antineoplastic agents include paclitaxel or doxorubicin.

Additional suitable chemotherapeutic agents include alkylating agents,antimitotic agents, plant alkaloids, biologicals, topoisomerase Iinhibitors, topoisomerase II inhibitors, and synthetics. AntiCancerAgents by Mechanism,http://www.dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999; Approved Anti-Cancer Agents,http://www.ctep.info.nih.gov/handbook/HandBookText/fda_agen.htm, pages1-7, Jun. 18, 1999; MCMP 611 Chemotherapeutic Drugs to Know,http//www.vet.purdue.edu/depts/bms/courses/mcmp611/chrx/drg2no61.html,Jun. 24, 1999; and Chemotherapy,http://www.vetmed.lsu.edu/oncology/Chemotherapy.htm, Apr. 12, 1999.

Representative alkylating agents include asaley, AZQ, BCNU, busulfan,bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil,chlorozotocin, cis-platinum, clomesone, cyanomorpholinodoxorubicin,cyclodisone, cyclophosphamide, dianhydrogalactitol, fluorodopan,hepsulfam, hycanthone, iphosphamide, melphalan, methyl CCNU, mitomycinC, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione,pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin,teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogenmustard, and Yoshi-864. AntiCancer Agents by Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative antimitotic agents include allocolchicine, HalichondrinM, colchicine, colchicine derivatives, dolastatin 10, maytansine,rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, tritylcysteine, vinblastine sulfate, and vincristine sulfate. AntiCancerAgents by Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative plant alkaloids include actinomycin D, bleomycin,L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate,mitramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine andtaxotere. Approved Anti-Cancer Agents,http://ctep.info.nih.gov/handbook/HandBook Text/fda_agent.htm, Jun. 18,1999.

Representative biologicals include alpha interferon, BCG, G-CSF, GM-CSF,and interleukin-2. Approved Anti-Cancer Agents,http://ctep.info.nih.gov/handbook/HandBookText/fda_agent.htm, Jun. 18,1999.

Representative topoisomerase I inhibitors include camptothecin,camptothecin derivatives, and morpholinodoxorubicin. AntiCancer Agentsby Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative topoisomerase II inhibitors include mitoxantron,amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine,bisantrene HCL, daunorubicin, deoxydoxorubicin, menogaril, N, N-dibenzyldaunomycin, oxanthrazole, rubidazone, VM-26 and VP-16. AntiCancer Agentsby Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative synthetics include hydroxyurea, procarbazine, o,p′-DDD,dacarbazine, CCNU, BCNU, cis-diamminedichloroplatimun, mitoxantrone,CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadeland porfimer sodium. Approved Anti-Cancer Agents,http://ctep.info.nih.gov/handbook/HandBookText/fda_agen.htm, Jun. 18,1999.

Representative antibodies include Monoclonal antibodies directed toproliferating cells such as Rituximab (anti-CD20) for B-cell tumors andherceptin.

Drugs in clinical trials for cancer are specifically contemplatedincluding, but not limited to: 715992 (kinesininhibitor)(GlaxoSmithKline); Advexin (Introgen Therapeutics); AG-002037(Pfizer); APC8024 (Dendreon); atrasentan (ABT-627); BIBH 1(Boerhinger-Ingelheim) CCI 779 (Wyeth Pharmaceuticals); CEA Vac (TitanPharmaceuticals); CEA-CIDE (Immunomedics) CEA-Scan (Immunomedics);Celebrex (Pharmacia); CP-547, 632 (anti-VEGF tyrosine kinase)(OSIPharmaceuticals); CP-724-714 (anti-ErbB2[HER-2 neu] tyrosine kinase)(OSIPharmaceuticals); CpG 7909 (Aventis Pharmaceuticals); dendritic/cancercell fusion (Genzyme Molecular Oncology); ERA 923 (tissue-selectiveestrogen receptor modulator-SERM) (Ligand Pharmaceuticals); Ethyol(MedImmune Oncology); fowlpox-(6D)-TRICOM/vaccinia-(6D)-TRICOM vaccine(National Cancer Institute); G-3139 (Genta); Gemzar (Eli Lilly);Genasense (Genta); GeneVax (Centocor); GPI-0100 immune enhancer(adjuvant)(Galencia Pharmaceuticals); GTI 2040 (Lorus Therapeutics); GTI2501 (Lorus Therapeutics); H11 (Viventia Biotech); interleukin-4 (IL-4)(National Cancer Institute); irofulven (National Cancer Institute);liquid IL-2 (Chiron); MAb antibody 3A1 (National Cancer Institute);multitargeted antifolate I (Eli Lily); Myocet (Liposome Company); oralpaclitaxel (IVAX Pharmaceuticals); P53 and RAS vaccine (National CancerInstitute); PD-183805 (Pfizer); Proleukin (Chiron); ProMune (Chiron);R1550 (Antisoma); RAS peptides (National Cancer Institute); rebeccamycinanalog (National Cancer Institute); recombinant human chorionicgonadotropin (r-hCG) (Serono); RSR-13 (Allos Therapeutics); RSR-13 (EliLilly); Targretin (Ligand Pharmaceuticals); tariquidar (QLT); Taxotere(Aventis Pharmaceuticals); TLK286 (Telik); vaccina-MUC-1 vaccine(Therion Biologics); vaccinia-MUC-1 vaccine (National Cancer Institute);Xtotax (Cell Therapeutics); Xyotax (Cell Therapeutics); Yondelis(ET-743)(Johnson & Johnson); Zarnestra (Johnson & Johnson); ZD6126 andZD6474 (AstraZeneca); and Zoladex (AstraZeneca)

Processes for the Preparation of the Compounds

Modular synthetic processes directed to the synthesis of the resorcylicacid lactones of the invention are presented below. The synthesesdeveloped may utilize resin-assisted or solid phase synthesis tominimize and facilitate the isolation of intermediate and finalproducts.

The following abbreviations are used herein.

Ac Acetyl (CH₃C═O)

BBN Borabicyclononane

Bn Benzyl

Bz Benzoyl

Cy₃ Cyanine dye labeling reagent

δ Chemical shift (NMR)

DCC Dicyclohexylcarbodiimide

DEAD Diethyl azodicarboxylate

DIAD Diisopropyl azodicarboxylate

d.e. Diastereoisomeric excess

DIBAL or Dibal-H Diisobutylaluminum hydride

DIC N,N′-diisopropylcarbodiimide

DMAP 4-Dimethylaminopyridine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

EC₅₀ Plasma concentration required for obtaining 50% of maximum effectin vivo

e.e. Enantiomeric excess

EOM Ethoxymethyl (CH₃CH₂OCH₂—)

FDA Food and Drug Administration

Grubbs' II Grubbs' second generation catalyst:(ruthenium[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolinylidene)dichloro(phenylmethylene)(tricyclohexylphosphane)

HFIP HexafluoroisopropanolHPLC High performance chromatographyHRMS High resolution mass spectrometryHSP90 Heat shock protein 90Hunig's Base DiisopropylethylamineIC₅₀ Concentration of a drug that is required for 50% inhibition invitroIpc₂ Bis-isopinocamphorylJ Coupling constantLDA Lithium diisopropylamideμM Micromolar concentration (μmol·l⁻¹)M.S. Mass spectrumNMR Nuclear magnetic resonancePG Protecting GroupPS- Polymer supportedPS-DCC Polymer supported dicyclohexylcarbodiimidePS-TBD (1,5,7)-Triaza-bicyclo[4.4.0]dodeca-5-ene-7-methyl polystyrenePyr or Py Pyridinerac RacemicRAL Resorcylic acid lactoneRCM Ring-closing metathesisR_(f) Retention factorRT Room temperatureSEM 2-TrimethylsilylethoxymethoxyTBAF Tetra-n-butylammonium fluorideTBAI Tetra-n-butylammonium iodideTBDPS t-ButyldiphenylsilylTBS t-ButyldimethylsilylTFA Trifluoroacetic acidTFAA Trifluoroacetic acetic anhydrideTHF TetrahydrofuranTHP TetrahydropyranTLC Thin layer chromatographyTMS TrimethylsilylTMSCl TrimethylsilylchlorideTNTU 2-(endo-5-norbornene-2.3-dicarboxylimide)-,1,3,3-tetramethyluronium tetrafluoroborateTs Tosyl (p-CH₃C₆H₄SO₂)p-TSOH para-Toluenesulfonic acid

A general retrosynthetic disconnection of the synthetic strategy forpreparation of the compounds of the invention is shown below (seeBarluenga et al., Angew. Chem. Int. Ed., 2008, 47, 4432-4435). AMitsunobu esterification, an acylation and a ring-closing metathesis areshown as the main disconnections using three building blocks. Usingthese building blocks and synthetic strategy, a divergent synthesis ofthe compounds was developed. A similar strategy has been used to preparea library of pochonin analogues with HSP90 activity (see Moulin et al.,Chem. Eur. J. 2006, 12, 8819).

Retrosynthetic Analysis for Compounds of the Invention

The schemes illustrated below are non-limiting examples of the synthesisof the compounds of the invention and intermediates used to prepare thecompounds. It will be apparent to one of skill in the art that thereactions depicted in the schemes may use alternate reagents andconditions to achieve the desired transformation. For example, variousprotecting groups may be used in the synthesis of the compounds, and thespecific groups depicted in the schemes are non-limiting examples. Forexample, any suitable protecting groups for hydroxy and carboxyl groupstaught in Greene et al., Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) Ed., 1999 may be used instead of the protectinggroups shown. Furthermore, alternate reagents known in the art for thetransformations shown, including, for example, the esterification of thearomatic carboxylic acid or the ring closure reaction may be used.

Scheme 1 below shows the general synthetic protocol for one of thecompounds of the invention where X═O and n=1, starting from intermediate1-1, which is formed from readily available protected aromaticprecursors by acylation of the benzylic position with a suitablysubstituted carboxylic acid derivative followed by formation of thesubstituted oxime by reaction of the acylated aromatic group with asuitable hydroxylamine reagent, such as aminooxyacetic acid. Scheme 2below provides a non-limiting example of the preparation of an aromaticcompound of structure 1-1.

To facilitate the isolation and purification of the intermediates andfinal compounds, intermediates such as compound 1-1 may be anchored ontoa suitably functionalized resin, such as a 2-chlorotrityl resin, byreaction of the carboxylic acid group with the resin. The resin-anchoredintermediate 1-2 is deprotected to provide intermediate 1-3 with thefree carboxylic acid group.

The carboxylic acid 1-3 is reacted with a suitable alcohol R²OH, whichcomprises a double bond that may be utilized for a ring-closingmetathesis reaction with a suitable catalyst. Various conditions for theformation of an aromatic ester derivative may be used, including, butnot limited to a Mitsunobu esterification with, for example, ahomoallylic alcohol, to form the corresponding ester (not shown). Theresin bound ester is then treated with a catalyst, such as Grubb'ssecond generation catalyst, to effect ring closure to intermediate 1-4.Use of microwave irradiation during the ring closure has been found toimprove the efficiency of the metathesis reaction.

It is important to note that the reaction sequence is not possible inthe absence of the oxime functionality, since reaction of thecorresponding benzylic ketone results in coumarin byproducts (seeBarluenga et al., Chem. Eur. J. 2005, 11, 4935).

The macrocycles are removed from the resin using, for example,hexafluoropropanol (HFIP) to provide the oxime acid product 1-5. Use ofthe mild HFIP for the removal of the compounds from the resin left theEOM protecting groups in tact, thus enabling further elaboration ofother functionality on the macrocycles. The resulting product may bederivatized by reaction of the free carboxylic acid with a suitablegroup. Carboxylic acids are very useful for the formation of variousderivatives, as known in the art. The free carboxylic acid may bederivatized by reacting with a variety of compounds to form desiredproducts. For example, reaction with R⁴XH (X═O or NH), in the presenceof an activating reagent, such as dicyclohexylcarbodiimide (DCC) or analternate activating reagent, to form the corresponding ester or amide1-6.

In non-limiting examples, the free carboxylic acid in compound 1-5 maybe reacted with an amine or alcohol to form an amide or ester. In someembodiments, the amines shown below are used to form compounds of theinvention. It will be apparent that alternate groups may be used to formthe corresponding amide or ester.

The use of resin-immobilized carbodiimide and sulfonic acid wasadvantageously used to form various amides and esters from thecarboxylic acid moiety liberated upon removal of the macrocycles(compounds 1-5) from the resin.

Scheme 2 shows an example synthesis of intermediate 1-1 from a suitablyprotected aromatic carboxylic acid derivative 2-1. Deprotonation of 2-1with lithium diisopropylamide (LDA) and reaction with Weinreb amide 2-2followed by quenching with benzoic acid resin affords intermediate 2-3.Reaction of 2-3 with excess hydroxyl amine reagent results in formationof the oxime intermediate 2-4, which is utilized further, as describedin scheme 1.

In some embodiments non-limiting embodiments, the starting aromaticstarting material may be the compound shown below, where R¹ is H orhalogen, particularly hydrogen and chloro. As discussed, otherprotecting groups known in the art may be used for the phenol andcarboxyl functional groups.

Homoallylic Alcohols

A variety of homoallylic alcohols are commercially available and may beused in the synthesis. Other homoallylic alcohols bearing varioussubstituents may prepared by methods known in the art. Scheme 3 belowillustrates a synthesis of various homoallylic alcohols that are notcommercially available. In one embodiment, the homoallylic alcohols 3-3were obtained in their highest enantiomeric form either by enzymaticresolution of the racemic alcohol (H. E. Master et al., Tet. Lett.,37:9253 (1996); S. Singh et al., Tet. Asymm., 13:2679 (2002) or viaBrown allylation of the corresponding aldehyde (H. C. Brown and P. K.Jadhav J. Am. Chem. Soc., 105:2092 (1983). The phenyl (3-3a), thepyridinyl (3-3b) and the furyl (3-3c) alcohols were prepared byenzymatic resolution (Scheme 3). Racemic alcohols 3-2a-c were obtainedafter Grignard addition of commercially available allylmagnesium bromideon their corresponding aldehyde 3-1a-c.

Kinetic enzymatic resolution of racemic alcohols 3-2a-c was realizedusing the highly efficient Amano lipase (an immobilized version ofPseudomonas cepacia). This enzyme catalyzed a selectivetransesterification of alcohols (R)-3-2a-c with vinyl acetate as an acyldonor, the (S) alcohols 3-2a-c being isolated in excellent yields andgood enantiomeric excesses (Table 2).

TABLE 2 Enantioselective acylation of alcohols rac-3-2a-c bytransesterification with lipase Conv. Yield Ratio (%) e.e. Yield e.e.Time (%) (S)- (%) (%) (%) Entry Substrate (h) (OH/OAc) 3-2 (S)-3-2(R)-3-2 (R)-3-2 1 rac-3-2a 30 50:50 45 98 49 93 2 rac-3-2b 30 52:48 5089 39 94 3 rac-3-2c 5 49:51 44 88 49 89

Enantiomeric excess obtained with this methodology are all above 88%.Acetylated alcohols (R)-3-3 were then hydrolysed to the correspondingalcohols (R)-3-2a-c in excellent yields. Scheme 4 below illustrates analternate process based on Brown allylation for the synthesis of theisopropyl (4-4d), the propyl (4-4e) and the benzyl (4-4f) alcohols(Scheme 4).

(−)-B-Allyldiisopinocampheylborane (4-2, (−)-Ipc₂BAllyl) was synthesizedin a three steps sequence from (−)-α-pinene involving a hydroboration,the formation of the corresponding MeO-borinic ester 4-1 and itstreatment with a Grignard reagent. Further condensation on aldehydes4-3d-f followed by oxidation of the resulting borinates with alkalinehydrogen peroxide allowed the formation of the chiral homoallylicalcohols 4-4d-f in good enantiomeric excess.

In some embodiments of the invention, homoallylic amines may be usedrather than the alcohols. The corresponding amines may be readilyprepared from the alcohol by methods known in the art. In someembodiments of the invention, the homoallylic alcohols and amines shownbelow may be used in the preparation of the compounds of the invention.

Weinreb Amides

A wide variety of Weinreb amides may be used to prepare the compounds ofthe invention. Weinreb amides are well known in the art, and manyWeinreb amides or reagents for the preparation of Weinreb amides arecommercially available. Further, methods for the preparation of Weinrebamides are know. For example, a variety of Weinreb amides may beprepared by reacting an aldehyde with the desired functionality with aWeinreb amide ylide (compound 5-4, Scheme 5) or a Weinreb amidephosphonate (compound 6-6, Scheme 6) to form the desired α,β-unsaturatedWeinreb amide. In one embodiment, a Weinreb amide comprising a protectedhydroxy group is prepared according to Scheme 5 below.

Trans-3-hexenedioic acid dimethyl ester 5-1 was reduced to thecorresponding diol with lithium aluminum hydride. The diol wasmono-protected as the tert-butyldiphenylsilyl ether 5-2, and the freealcohol was converted to aldehyde 5-3 in three steps via the nitrile.Aldehyde 5-3 was then treated with Weinreb amide ylide 5-4 to producethe diene Weinreb amide 5-5. Various other Weinreb amides may beprepared using compound 5-4 and an aldehyde with the desiredfunctionality.

In another embodiment, Weinreb amides containing a hydroxy substituentmay be produced using the synthetic process shown in Scheme 6.

Treatment of t-butylacetate 6-1 with a bulky base, such as LDA, andreaction of the resulting enolate with a vinyl aldehyde provides alcohol6-2. The racemic alcohol is resolved by treatment with amino lipase PS-CII to produce the chiral acetate 6-3 and the chiral alcohol 6-4. Thehydroxy group is suitably protected, for example as thet-butyldimethylsilyl ether 6-5, and the corresponding aldehyde isproduced by reaction with DIBAL-H. Reaction with the Weinreb phosphonate6-6 provides the desired Weinreb amide 6-7.

In non-limiting embodiments, the Weinreb amides shown below may be usedto prepare certain compounds of the invention.

Alkylation of aromatic components such as 2-1 (Scheme 1) with Weinrebamides substituted with a protected hydroxy group or other protectedfunctional group, allow the preparation of compounds comprising aprotected hydroxy group on the macrocyclic ring, after deprotection. Thehydroxy group may be derivatized to produce a variety of compounds ofthe invention.

Scheme 7 below illustrates various compounds of the invention preparedfrom a hydroxy-substituted macrocycle, which is obtained from acorresponding Weinreb amide comprising a protected hydroxy group, suchas 6-7. The silyl-protected hydroxy group in compound 7-1 is selectivelydeprotected to provide compound 7-2 with a free hydroxy group. Thenucleophilic hydroxy group in compound 7-2 may be reacted with variousreagents to provide derivatized compounds, such as amide 457/458 andazido-substituted compound 459/460. It will be apparent that variousother derivatized compounds may be prepared by reacting the freehydroxyl group with a variety of reagents to produce the correspondingderivatized macrocycles of the invention.

In another embodiment of the invention, compounds of the inventionsubstituted with an azido group, such as compounds 459/460, may befurther elaborated to provide amino-substituted macrocycles by reductionof the azido group. Scheme 8 illustrates the preparation of anamino-substituted compound and the use of the compound for the synthesisof certain amide-containing derivatives. It will be apparent to one ofskill in the art that the preparation of amino-substituted macrocyclesprovides a handle for substitution of the macrocycles with a variety offunctional groups by reaction with the nucleophilic amino group.

Reduction of the azido group may be accomplished by various methods,including by treatment with triphenylphosphine, to provide theaminoalkyl-substituted compound 8-1. Use of Weinreb amide intermediatescontaining an azido group result in compounds with an azidofunctionality at another position of the macrocycle. The other azidesubstituted compounds may also be elaborated analogously to produceamino groups. Reaction of the free amino group of 8-1 provides access toa variety of compounds. For example, reaction of the amino group withacetic anhydride yields compound 461, and reaction with an cyaninelabeling reagent provides compound 462, containing a fluorophore (seeErnst et al., Cytometry, 1989, 10(1), 3-10).

Alternatively, hydroxy-substituted macrocycles may be prepared byallylic oxidation of the macrocycle, as illustrated in Scheme 9.Treatment of a protected macrocycle, such as compound 9-1 with seleniumdioxide in ethanol provides the hydroxy-substituted product as a mixtureof isomers. The resulting alcohols may be further derivatized, asdiscussed above, to provide a variety of compounds of the invention.Scheme 9 illustrates the formation of allyl ethers 449 by reaction ofthe alcohol products with allyl chloride in the presence of a base, suchas sodium hydride and subsequent removal of the phenol protectinggroups.

Biological Activity

The library of macrocycles was assayed for its cytotoxicity in HCC1954and SK-BR-3 tumor cells. Compounds showing significant cytotoxicity werefurther examined for their ability to induce degradation of known HSP90client proteins such as ErbB2 in SK-BR3. Thus, after 18 hrs treatmentwith the compounds, the whole cell protein lysates were obtained,protein concentrations were normalized and the concentration of ErbB2was quantified by Western blotting (C. Chavany et al J. Biol. Chem.271:4974-4977 (1996)). Several compounds from the library were moreeffective than radicicol and 17-AAG in reducing ErbB2 concentration. Forexample compounds 13a, 13b and 13c in the form of the E-oxime isomer wassignificantly more effective than both radicicol and 17-AAG.

Based on the in vitro data (see Table 3, Example 9), compound 13a wasfurther evaluated in vivo with CB17/SCID mice with a xenograft bearingBT-474 (breast tumor cell line) was used, as this cell line has beenshown to respond to HSP90 inhibitors in an animal model (Basso et al.,Oncogene 2002, 21, 1159). Two schedules of 100 mg every other day (q2d)or every four days (q4d) during 28 days were investigated. The treatmentwith compound 13a resulted in a dose-dependent inhibition of the tumorgrowth with an 18% regression in tumor volume using the q2d schedule.The results are shown in FIG. 1. Neither the q2d nor the q4d schedulesresulted in significant weight loss (FIG. 1). Histologic examination oftumors removed from animals receiving either the vehicle (DMSO) or drugfor 28 days following the q2d schedule revealed a dramatic loss ofcellularity in tumors obtained from drug-treated animals. Nuclei ofremaining cells were uniformly condensed, suggesting the occurrence ofmassive apoptosis (sec FIG. 2, top panels). This was confirmed by thehigh degree of nuclear TUNEL staining seen in tumors excised from drugtreated animals, which is shown in FIG. 2, bottom panels. These datasuggest that tumor regression in animals treated for 28 days accordingto the q2d schedule may be more dramatic than estimated with tumorvolume measurements, since few to no viable cells could be identified atthe end of the treatment period.

EXAMPLES

General Techniques. All reactions were carried out under a nitrogenatmosphere with dry (anhydrous) solvents under anhydrous conditions,unless otherwise noted. Anhydrous solvents were obtained by passing themthrough commercially available alumina column (Innovative Technology,Inc.,® VA). All substituted polystyrene resins (100-200 mesh, 1% DVB)were purchased from Novabiochem® or Aldrich®. The Grubbs' II catalystwas purchased from Materia Inc.® Solid phase reactions were carried on aQuest® 210 or round bottom flasks and filtered in fritted funnels.Reactions were monitored by thin layer chromatography (TLC) carried outon 0.25 mm E. Merck® silica gel plates (60F-254) using UV light asvisualizing agent and 10% ethanolic phosphomolybdic acid or vanillinsolution and heat as developing agents. E. Merck® silica gel (60,particle size 0.040-0.063 mm) was used for flash column chromatography.PTLC (preparative thin layer chromatography) were carried out on 0.25 mmE. Merck® silica gel plates. NMR spectra were recorded on a BrukerAdvance-400® instrument and calibrated by using residual undeuteratedsolvent as an internal reference. The following abbreviations were usedto explain the multiplicities: s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet, b=broad. IR spectra were recorded on aPerkin-Elmer 1600 series FT-IR spectrometer. LC-MS were recorded usingan Agilent 1100® HPLC with a Bruker® micro-TOF instrument (ESI). Unlessotherwise stated, a Supelco® C8 (5 cm×4.6 mm, 5 μm particles) column wasused with a linear elution gradient from 100% H₂O (0.5% HCO₂H) to 100%MeCN in 13 min at a flow rate of 0.5 ml/min. Unless otherwise stated,LDA was prepared at a concentration of 0.566 M by treating a solution ofdiisopropylamine (1.0 equiv.) in THF at −78° C. with n-butyllithium (1.0equiv.) and stirred for 30 min at this temperature before use.

Example 1: Preparation of Weinreb Amides

As discussed above, many Weinreb amides used to prepare the compounds ofthe invention are prepared by methods known in the art. Characterizationdata is shown below for selected Weinreb amides used to prepare thecompounds of the invention.

¹H NMR (400 MHz, CDCl₃, 25° C.): δ=7.33 (dd, J=15.3, 11.0 Hz, 1H), 6.52(m, 2H), 5.61 (d, J=16.6 Hz, 1H), 5.48 (d, J=10.2 Hz, 1H), 3.73 (s, 3H),3.27 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, 25° C.): δ=166.8, 143.4, 135.1,124.7, 119.7, 61.7, 32.3; IR (film): ν_(max)=2936, 1658, 1598, 1427,1382, 1181, 1095, 1005 cm⁻¹.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 5.40-5.26 (m, 2H), 3.67 (s, 3H), 3.17(s, 3H), 2.41 (t, J=7.4 Hz, 2H), 2.11-1.97 (m, 4H), 1.64 (tt, J=8.7 Hz,J=6.3 Hz, 2H), 1.39 (tt, J=8.6 Hz, J=6.7 Hz, 2H), 0.95 (t, J=7.8 Hz,3H); ¹³C NMR (CDCl₃, 100 MHz, 25° C.) δ 131.9, 128.7, 61.2, 31.8 (×2),29.5, 26.9, 24.3, 20.5, 14.3, one quaternary carbon is missing.

¹H NMR (CDCl₃, 400 MHz) δ 5.90 (s, 1H), 5.54-5.60 (m, 1H), 4.82 (d,J=17.0 Hz, 1H), 4.75 (d, J=10.1 Hz, 1H), 3.43 (s, 3H), 2.96 (s, 3H),2.02 (m, 4H), 1.90 (s, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ 137.55, 115.09,114.22, 61.36, 40.26, 31.67, 18.64.

1H NMR (CDCl₃, 400 MHz, 25° C.) δ 6.93 (dt, J=15.5, 7.6 Hz, 1H); 6.39(d, J=15.5 Hz, 1H); 5.70-5.79 (m, 1H), 4.94-5.02 (m, 2H); 3.69 (s, 3H);3.23 (s, 3H); 2.18-2.36 (m, 3H); 1.02 (d, J=9.9 Hz, 3H).

1H NMR (CDCl₃, 400 MHz, 25° C.) δ 6.93 (dt, J=15.5, 7.6 Hz, 1H); 6.39(d, J=15.5 Hz, 1H); 5.70-5.79 (m, 1H), 4.94-5.02 (m, 2H); 3.69 (s, 3H);3.23 (s, 3H); 2.18-2.36 (m, 3H); 1.02 (d, J=9.9 Hz, 3H).

Example 2: Preparation of Hydroxy-Substituted Weinreb Amides

Weinreb amides containing a protected hydroxy group are preparedaccording to the procedure depicted in Scheme 6 and described below,starting with the preparation of racemic alcohols 6-2.

To the solution of freshly prepared LDA (0.56 M, 60 mmol) at −78° C.under nitrogen was added solution of t-butyl acetate (8.1 mL, 60 mmol,1.0 equiv.) in THF (10 mL) dropwise. After a further one hour at −78°C., acrolein (4.5 mL, 60 mmol, 1.0 equiv.) in THF (5 mL) was added andthe reaction was kept stirring at the same temperature for 5 min. Thereaction was quenched with saturated NH₄Cl solution and extracted withethyl acetate (150 mL×3), the combined organic phase was washed by brine(120 mL), dried over anhydrous Na₂SO₄, and evaporated. The residueunderwent flash chromatography column (PE/EA, 8/1) to give the desiredcompound (8.35 g, 81%). ¹H (CDCl₃, 400 MHz, 25° C.) δ 5.82-5.91 (dt,1H); 5.30 (dd, J=17.2 Hz, J=0.8 Hz, 1H); 5.14 (dd, J=10.4 Hz, J=0.8 Hz,1H); 4.48 (m, 1H); 3.13 (d, 1H); 2.46 (m, 2H); 1.46 (s, 9H). ¹³H NMR ofwh3-27 (CDCl₃, 400 MHz, 25° C.) δ 171.5, 138.9, 114.9, 81.2, 68.9, 42.1,28.0

To the solution of the previously prepared racemic alcohol (8.35 g, 48.5mmol) in vinyl acetate (120 mL) was added Amino lipase PS-C II (750 mg,15 mg/mmol) at 30° C. The reaction was stirred for 60 hrs. Afterfiltration, the solution was concentrated and underwent flashchromatography column (PE/EA, 15/1 to 5/1) to give the desired compound(3.86 g) in the yield of 46%. To a solution of this chiral alcohol (3.75g, 21.7 mmol) in DMF (60 mL) at 0° C. under nitrogen atmosphere, wasadded imidazole (2.96 g, 43.5 mmol, 2.0 equiv.) and TBSCl (3.93 g, 26.0mmol, 1.2 equiv.), then the reaction was allowed to warm to 23° C. andstirred for 5 hrs. The reaction was extracted from saturated NH₄Clsolution with ethyl acetate (100 mL×3), washed by brine (100 mL), driedover anhydrous Na₂SO₄. After removal of the solvent, the residueunderwent flash column (PE/EA, 50/1) to obtain the TBS protected alcohol(5.85 g, 93%). ¹H (CDCl₃, 400 MHz, 25° C.) δ 5.79-5.88 (dt, 1H); 5.20(dd, J=16.0 Hz, J=2.8 Hz, 1H); 5.05 (dd, J=10.4 Hz, J=2.8 Hz, 1H);4.51-4.56 (m, 1H); 2.46 (dd, 1H); 2.34 (dd, 1H); 1.44 (s, 9H); 0.88 (s,9H); 0.05 (d, 6H). ¹³C NMR (CDCl₃, 400 MHz, 25° C.) δ 170.3, 140.5,114.4, 80.4, 70.9, 44.8, 28.1, 25.8, 18.1, −4.4, −5.0.

To the solution of the ester prepared in the precedent procedure (5.85g, 20.4 mmol) in CH₂Cl₂ (100 mL) under nitrogen atmosphere, DIBAL (24.5mL, 1M in toluene, 1.2 equiv.) was added at −78° C. and the reaction waskept stirring at the same temperature for half an hour. Then saturatedtartrate salt solution (100 mL) was added to the reaction and stirredfor 2 hrs until the system turned clear. The two phases were separatedand extracted by CH₂Cl₂ (100 mL×2), washed by brine, dried over Na₂SO₄.After removal of the solvent, the residue (4.33 g) obtained was used forthe next step without further purification. To the solution of thealdehyde (4.33 g) in CH₂Cl₂ (100 mL) was added Wittig reagent (7.33 g,20.2 mmol, 1.0 equiv.) at 23° C. The reaction was stirred overnight.After removal of the solvent under reduced vacuum, the residue underwentflash chromatography (PE/EA=20:1, then 10/1, 3/1) afforded the desiredcompound (4.25 g) in the yield of 71% for the two steps. ¹H (CDCl₃, 400MHz, 25° C.) δ 6.89-6.96 (dt, 1H); 6.41 (d, 1H); 5.77-5.85 (m, 1H); 5.18(dd, 1H); 5.05 (dd, 1H); 4.23 (dd, 1H); 3.67 (s, 3H); 3.22 (s, 3H); 2.42(dd, 2H); 0.88 (s, 9H); 0.03 (d, 6H). ¹³C (CDCl₃, 400 MHz, 25° C.) δ166.6, 143.5, 140.6, 120.9, 114.3, 72.7, 61.6, 41.4, 32.3, 25.8, 18.2,−4.5, −4.9.

Example 3: Aromatic Components

Various suitably protected aromatic groups are used in the invention.Methods for the preparation of suitable resorcylic acid lactones for thepreparation of the macrocycles are known in the art. For example,International Publication No. WO 2008/021213, which is incorporated byreference in its entirety, describes synthetic methods for a variety ofderivatives of resorcylic acid, which can be used to prepare thecompounds of the invention. Selected characterization data for aromaticcompounds used in the invention are provided below.

¹H NMR of ester (CDCl₃, 400 MHz, 25° C.) δ 6.69 (s, 1H); 6.52 (s, 1H);5.19 (s, 2H); 5.17 (s, 2H); 4.37 (t, 2H); 3.66-3.74 (m, 4H); 2.28 (s,3H); 1.18-1.25 (m, 6H); 1.09 (t, 2H); 0.05 (s, 9H).

¹H NMR of ester (CDCl₃, 400 MHz, 25° C.) δ 6.98 (s, 1H); 5.28 (s, 2H);5.19 (s, 2H); 4.39 (t, 2H); 3.76 (q, 2H); 3.70 (q, 2H); 2.32 (s, 3H);1.19-1.23 (m, 6H); 1.10 (t, 2H); 0.05 (s, 9H)

Example 4: Alkylation Intermediates

The preparation of alkylation intermediates derived from resorcylic acidaromatic derivatives and Weinreb amides is illustrated in Scheme 2.Various different alkylation intermediates, with varying substitution onthe aromatic ring and the macrocycle, may be used to prepare thecompounds of the invention. These compounds may be prepared from thedesired aromatic component and Weinreb amide according to the processdepicted in the scheme. Characterization data of selected alkylationintermediates used in the preparation of the compounds of the inventionis provided below.

¹H NMR two isomers (1:1) (CDCl₃, 400 MHz, 25° C.) δ 9.52 (w×2, 2H); 7.04(s×2, 2H); 6.69 (d, J=16.1 Hz, 1H); 6.26 (dt, J=16.1, 7.0 Hz, 1H); 5.97(dt, J=16.1, 7.0 Hz, 1H); 5.76 (d, J=16.1 Hz, 1H); 5.53-5.71 (m, 2H);5.28 (s×2, 4H); 5.18 (s, 2H); 5.17 (s, 2H); 4.91-4.96 (m, 2H); 4.81-4.84(m, 2H); 4.65 (s, 2H); 4.49 (s, 2H); 4.27-4.33 (m, 4H); 4.02 (s, 2H);3.87 (s, 2H); 3.67-3.77 (m, 8H); 1.98-2.26 (m, 6H); 1.17-1.22 (m, 12H);0.99-1.06 (m, 4H); 0.96 (d, J=6.4 Hz, 3H); 0.82 (d, J=6.4 Hz, 3H); 0.05(s, 9H); 0.03 (s, 9H).

¹H NMR of two isomers (2:1) (CDCl₃, 400 MHz, 25° C.) δ 9.47 (w×2, 2H);6.75 (d, J=2.0 Hz, 1H); 6.71 (d, J=2.1 Hz, 1H); 6.67 (d, J=16.1 Hz, 1H);6.57 (d, J=2.1 Hz, 1H); 6.48 (d, J=2.0 Hz, 1H); 6.21 (dt, J=16.1, 7.0Hz, 1H); 6.03-6.11 (m, 2H); 5.54-5.68 (m, 2H); 5.19 (s×2, 4H); 5.17 (s,2H); 5.15 (s, 2H); 4.82-4.88 (m, 4H); 4.67 (s, 2H); 4.66 (s, 2H);4.36-4.40 (m, 4H); 3.88 (s, 2H); 3.65-3.74 (m, 10H); 2.06-2.21 (m, 6H);1.17-1.23 (m, 12H); 1.07-1.12 (m, 4H); 0.91 (d, J=6.4 Hz, 3H); 0.86 (d,J=6.4 Hz, 3H); 0.07 (s, 9H); 0.06 (s, 9H)

Example 5: Preparation of Macrocyclic Compounds of the Invention

General Procedure for the Synthesis of Compounds of the Invention

The general synthesis of the macrocycles described below is depicted inScheme 1, starting from carboxylic acid 1-1. To a suspension of 3.0equiv of polystyrene based chlorotrityl resin (1.1 mmol/g) in CH₂Cl₂ atroom temperature were added 6.0 equiv of Hunig's base and 1.0 equiv ofthe corresponding acid 1-1 (Scheme 1). After shaking the mixture for 24hours, the different resins were capped with acetic acid for another 24hours. After this time the resins were washed with CH₂Cl₂, DMF, CH₂Cl₂and Et₂O, then dry and re-suspended in THF. To these suspensions, 4.0equiv. of TBAF (1M) were added and the mixtures were shaken for 4 hours.The resins were then filtered and washed thoroughly using THF, CH₂Cl₂,1% AcOH in CH₂Cl₂, CH₂Cl₂, Et₂O several times. The completion of thedeprotection and total elimination of the tetrabutyl ammonium salts wasassessed by LC-MS after cleavage of a very small portion of each resinusing a solution of HFIP in CH₂Cl₂ ¼ for 30 min (LC-MS were recordedusing an Agilent 1100 HPLC with a Supelco C8 (5 cm×4.6 mm, 5 μmparticles) column using a linear elution gradient from 95% H₂O (0.5%HCO₂H) to 100% MeCN in 8 min at a flow rate of 0.5 mL/min). The resinswere split for further diversification with the different alcohols. TheMitsunobu reactions were carried in dry toluene using 5.0 equiv of thecorresponding alcohol R²OH, 2.0 equiv of Ph₃P and 2.0 equiv of DIAD andthe suspensions were agitated overnight. The productivity of theesterification reactions were assessed by LC-MS after cleavage of asmall portion as describe before and the pools which had not proceededto completion were re-subjected to the same conditions. After washingand drying the resins they were suspended in toluene and submitted tothe metathesis reaction. Grubbs' second generation catalyst was added toeach suspension (3×0.06 equiv) and the reactions were heated at 120° C.in a CEM microwave reactor for 3×45 min (fresh catalyst was added ineach cycle). The resins were then washed with CH₂Cl₂, DMF, CH₂Cl₂ andEt₂O several times. Then the compounds were cleaved from the resin usinga solution of HFIP in CH₂Cl₂ ¼ for 3 h (re-subjection of the resin tothe cleavage conditions afforded minimal quantities of compoundsuggesting the original cleavage had proceeded to completion) and thecorresponding products were purified by PTLC and isolated with yields inbetween 20 to 30% after 5 steps.

Each compound was dissolved CH₂Cl₂ and then aliquoted for furtheramidation. To each vial were added 2.0 equiv of the corresponding amine,3.0 equiv of PS-DCC (DCC polystyrene resin) and cat DMAP, and thesuspensions were stirred for over 72 h. The completion of each reactionwas monitored by LC-MS. The corresponding amides were filtered,evaporated and re-dissolved in methanol. To each solution were added 10equiv of sulfonic acid polystyrene resin and the suspensions werestirred for 4 h at room temperature. The final compounds were filteredand isolated with yields of 75 to 95%.

Characterization data for selected compounds of the invention areprovided below.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 11.64 (s, 1H), 6.64 (s, 1H), 6.01 (dt,J=15.5, 7.5 Hz, 1H), 5.11 (d, J=15.5 Hz, 1H), 5.10-5.03 (m, 2H), 4.85(s, 2H), 4.37 (t, J=4.8 Hz, 2H), 4.17 (s, 2H), 3.60 (t, J=5.0 Hz, 2H),3.46 (t, J=5.0 Hz, 2H), 2.34 (q, J=5.4 Hz, 2H), 2.10-2.02 (m, 2H),1.99-1.92 (m, 2H), 1.70-1.54 (m, 6H), 1 OH signal is not visible; ¹³CNMR (CDCl₃, 100 MHz, 25° C.) δ 170.27, 167.42, 163.21, 157.38, 155.18,138.21, 135.62, 131.82, 129.13, 124.76, 115.55, 107.60, 103.47, 72.63,65.03, 46.38, 43.31, 33.21, 32.76, 31.94, 31.84, 26.65, 25.64, 24.57;HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₄H₂₉ClN₂O₆Na: 499.1612. found:499.1638.

The geometry of the oxime was determined by x-ray diffraction. FIG. 3shows the Wire-frame representation of the crystal structure of 13a.

¹H NMR (CDCl₃, 400 MHz) δ 11.60 (s, 1H), 6.88 (d, J=1.9 Hz, 1H), 6.33(d, J=1.9 Hz, 1H), 6.14 (dt, J=16.1, 7.5 Hz, 1H), 5.83 (d, J=16.1 Hz,1H), 5.33 (m, 2H), 4.86 (s, 2H), 4.54-4.53 (m, 2H), 4.34 (s, 2H),3.58-3.55 (m, 2H), 3.40-3.38 (m, 2H), 2.51-2.48 (m, 2H), 2.11-2.07 (m,4H), 1.61-1.57 (m, 6H), 1 OH signal is not visible. ¹³C NMR (CD₃OD, 100MHz) δ 178.0, 175.8, 168.8, 166.6, 165.7, 147.1, 145.5, 141.0, 139.0,134.4, 122.6, 115.4, 110.4, 81.4, 73.2, 54.7, 51.6, 41.8, 41.3, 40.0,37.6, 35.5, 34.8, 33.5; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd forC₂₄H₃₀N₂O₆Na: 465.2002. found 465.2015.

The geometry of the oxime was determined by x-ray diffraction. FIG. 4shows the Wire-frame representation of the crystal structure of 13b.

¹H NMR (CDCl₃, 400 MHz) δ 11.27 (brs, 1H), 9.03 (brs, 1H), 6.54 (d,J=2.1 Hz, 1H), 6.34 (d, J=2.1 Hz, 1H), 6.05 (m, 1H), 5.68 (d, J=15.5 Hz,1H), 5.43 (m, 2H), 5.28 (m, 1H), 4.87 (d, J=14.5 Hz, 1H), 4.82 (d,J=14.5 Hz, 1H), 4.30 (d, J=15.5 Hz, 1H), 4.17 (d, J=15.5 Hz, 1H), 3.58(m, 2H), 3.41 (m, 2H), 2.68 (m, 1H), 2.24 (m, 2H), 2.04 (m, 3H), 1.61(m, 6H), 1.42 (d, J=6.4 Hz, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ 167.42,164.0, 161.85, 159.06, 141.91, 137.79, 132.77, 126.02, 124.63, 111.20,104.88, 102.10, 71.42, 71.27, 71.21, 45.92, 43.10, 37.82, 32.31, 30.49,30.24, 26.22, 25.32, 24.24, 18.92; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcdfor C₂₅H₃₂N₂O₆Na: 479.2158. found 479.2351.

The geometry of the oxime was deduced based on the x-ray diffraction ofthe Z isomer of 13c. FIG. 5 shows the Wire-frame representation of the Zisomer of 13c.

¹H NMR (CD₃OD, 400 MHz) δ 6.84 (d, J=16.1 Hz, 1H), 6.63 (d, J=16.1 Hz,1H), 6.51 (s, 1H), 6.46 (d, J=2.7 Hz, 1H), 6.21 (dt, J=16.1, 6.9 Hz,1H), 6.09 (dt, J=16.1, 7.5 Hz, 1H), 5.31-5.23 (m, 4H), 4.91 (d, J=13.3Hz, 2H), 4.60 (d, J=13.3 Hz, 2H), 4.45-4.39 (m, 4H), 4.18 (s, 4H), 3.76(m, 4H), 3.69-3.67 (m, 4H), 3.62-3.46 (m, 8H), 2.59-2.55 (m, 1H),2.45-2.43 (m, 5H), 2.37-2.33 (m, 4H), 2.15-2.14 (m, 2H), 4 OH signalsare not visible; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₃H₂₇ClN₂O₇Na:501.1405. found 501.1424.

¹H NMR (CD₃OD, 400 MHz) δ 6.64 (d, J=16.1 Hz, 1H), 6.53 (s, 1H), 6.48(s, 1H), 6.25 (dt, J=16.1, 7.5 Hz, 1H), 6.09 (dt, J=15.6, 7.5 Hz, 1H),5.52-5.48 (m, 2H), 5.33 (d, J=15.6 Hz, 1H), 5.26-5.24 (m, 2H), 4.94 (s,2H), 4.68 (s, 2H), 4.44-4.38 (m, 4H), 4.27 (s, 2H), 4.19 (s, 2H),3.97-3.93 (m, 4H), 3.86-3.76 (m, 4H), 3.34-3.33 (m, 4H), 3.39-3.20 (m,4H), 2.59-2.55 (m, 1H), 2.48-2.40 (m, 3H), 2.37-2.34 (m, 4H), 2.19-2.15(m, 2H), 2.10-2.06 (m, 2H), 4 OH and 2 NH are not visible; HRMS(MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₃H₂₈ClN₃O₆Na: 500.1564. found500.1590.

¹H NMR (DMSO-d6, 400 MHz, 25° C.) δ 10.2 (s, 1H), 6.45 (s, 1H), 6.44 (d,J=16.1 Hz, 1H), 6.12 (dt, J=16.1 6.4 Hz, 1H), 5.31-5.29 (m, 2H), 4.57(s, 2H), 4.16 (t, J=4.8 Hz, 2H), 3.70 (s, 2H), 3.35-3.30 (m, 4H), 2.31(m, 2H), 2.08-2.05 (m, 4H), 1.56-1.51 (m, 2H), 1.45-1.35 (m, 4H), 1 OHis not visible; ¹³C NMR (DMSO-d6, 100 MHz, 25° C.) δ 167.9, 166.3,155.4, 155.2, 153.4, 140.6, 134.3, 131.4, 119.4, 113.9, 112.4, 102.1,71.9, 65.2, 45.4, 42.1, 34.7, 31.8, 31.7, 30.9, 26.0, 25.9, 25.2, 24.0;HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₄H₂₉ClN₂O₆H: 499.1612. found499.1624.

The geometry of the oxime was deduced from structure 13a.

¹H NMR (CDCl₃, 400 MHz) δ 11.64 (s, 1H), 6.62 (d, J=16.1 Hz, 1H), 6.62(d, J=2.7 Hz, 1H), 6.33 (d, J=1.9 Hz, 1H), 6.25 (dt, J=16.1, 7.5 Hz,1H), 5.35 (m, 2H), 4.79 (s, 2H), 4.54-4.53 (m, 2H), 4.08 (s, 2H),3.56-3.54 (m, 2H), 3.38-3.37 (m, 2H), 2.50-2.48 (m, 2H), 2.12-2.08 (m,4H), 1.66-1.57 (m, 6H), 1 OH signal is not visible. ¹³C NMR (CDCl₃, 100MHz) δ 170.8, 167.9, 165.7, 162.0, 157.1, 143.1, 141.9, 132.2, 129.2,118.4, 110.4, 104.4, 102.5, 71.5, 64.5, 46.0, 43.3, 35.1, 32.9, 32.7,30.9, 26.4, 25.5, 24.5; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd forC₂₄H₃₀N₂O₆Na: 465.2002. found 465.2027.

The geometry of the oxime was deduced from structure 13b.

¹H NMR (CDCl₃, 400 MHz) δ 11.41 (s, 1H), 11.43 (s, 1H), 6.58 (s×2, 2H),5.56-5.43 (m, 4H), 4.53 (2×bs, 4H), 4.45-4.42 (m, 4H), 4.40 (2×d, J=16.6Hz, 2H), 3.86 (2×d, J=16.6 Hz, 2H), 3.52-3.50 (m, 4H), 3.46-3.41 (m,2H), 3.30 (s, 3H), 3.31 (s, 3H), 2.91 (dd, J=14.0, 8.3 Hz, 1H),2.89-2.85 (m, 1H), 2.52-2.51 (m, 4H), 2.41 (dd, J=14.0, 4.0 Hz, 1H),2.39-2.35 (m, 1H), 2.16-2.14 (m, 4H), 1.87-1.77 (m, 4H), 1.61-1.59 (m,4H), 1.49-1.43 (m, 12H), 2 OH signals are not visible; HRMS (MALDI-TOF)m/z [M+Na]⁺ calcd for C₂₅H₃₃ClN₂O₇Na: 531.1874. found 531.1894.

The oxime geometry was assigned by comparison to 14a.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 11.44 (s, 1H), 11.32 (s, 1H), 6.61 (s,1H), 6.57 (s, 1H), 5.55-5.42 (m, 2H), 5.38-5.35 (m, 2H), 4.77 (s, 2H),4.52 (s, 2H), 4.48-4.44 (m, 4H), 4.22 (s, 2H), 4.17 (s, 2H), 3.58-3.49(m, 4H), 3.31-3.28 (m, 4H), 2.50-2.46 (m, 2H), 2.42-2.36 (m, 4H),2.06-1.99 (m, 6H), 1.96-1.92 (m, 4H), 1.66-1.36 (m, 16H), 2 OH signalsare not visible; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for HRMS (MALDI-TOF)m/z [M+Na]⁺ calcd for C₂₄H₃₁ClN₂O₆Na: 501.1768. found: 501.1798.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 11.35 (s, 1H), 11.14 (s, 1H), 6.63 (s,1H), 6.56 (s, 1H), 6.48 (d, J=16.4 Hz, 1H), 6.00-5.99 (m, 2H), 5.85 (d,J=16.4 Hz, 1H), 5.37 (s, 2H), 5.15 (s, 2H), 5.14-5.09 (m, 8H), 4.68 (s,2H), 4.63 (s, 2H), 3.76 (t, J=5.0 Hz, 2H), 3.66 (t, J=4.7 Hz, 2H),3.52-3.48 (m, 2H), 3.39-3.36 (m, 2H), 2.52-2.48 (m, 2H), 2.41-2.32 (m,4H), 2.30-2.27 (m, 2H), 2.15-2.10 (m, 4H), 4 OH signals and 2 NH signalsare not visible; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for HRMS (MALDI-TOF)m/z [M+Na]⁺ calcd for C₂₁H₂₅ClN₂O₇Na: 475.1248. found: 475.1275.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 11.46 (s, 1H), 11.02 (s, 1H), 6.65 (s,1H), 6.65 (d, J=16.6 Hz, 1H), 6.60 (s, 1H), 6.48 (d, J=15.6 Hz, 1H),6.08-6.00 (m, 2H), 5.34-5.25 (m, 4H), 5.16-5.12 (m, 4H), 5.14 (s, 2H),5.10 (s, 2H), 4.72 (d, J=16.1 Hz, 1H), 4.65 (d, J=16.1 Hz, 1H), 4.41 (d,J=17.7 Hz, 1H), 4.15 (d, J=17.7 Hz, 1H), 2.91 (d, J=4.8 Hz, 3H), 2.78(d, J=4.8 Hz, 3H), 2.59-2.52 (m, 1H), 2.51-2.38 (m, 1H), 2.24-2.12 (m,4H), 2.07-2.00 (m, 4H), 1.95-1.87 (m, 2H), 2 OH signals and 2 NH signalsare not visible; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for HRMS (MALDI-TOF)m/z [M+Na]⁺ calcd for C₂₀H₂₃ClN₂O₆Na: 445.1143. found: 445.1178.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 11.32 (s, 1H), 11.04 (s, 1H),7.32-7.29 (m, 10H), 6.61 (s, 1H), 6.57 (s, 1H), 6.42 (d, J=16.4 Hz, 1H),6.07 (dt, J=15.8, 6.7 Hz, 1H), 5.99 (dt, J=16.4, 7.3 Hz, 1H), 5.67 (d,J=15.8 Hz, 1H), 5.37-4.95 (m, 8H), 4.73 (s, 2H), 4.69 (s, 2H), 4.64 (s,2H), 4.56 (s, 2H), 4.54 (s, 2H), 4.52 (s, 2H), 2.34-2.25 (m, 6H),2.12-2.05 (m, 4H), 2.00-1.99 (m, 2H), 2 OH signals and 2 NH signals arenot visible; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for HRMS (MALDI-TOF) m/z[M+Na]⁺ calcd for C₂₆H₂₇ClN₂O₆Na: 521.1456. found: 521.1498.

¹H NMR (acetone-d6, 400 MHz, 25° C.) δ 6.62 (d, J=15.8 Hz, 1H), 6.56 (s,1H), 6.27 (s, 1H), 6.14 (dt, J=15.8, 8.5 Hz, 1H), 6.02 (dt, J=15.5, 7.6Hz, 1H), 5.37-5.34 (m, 5H), 5.26 (s, 1H), 5.22 (s, 1H), 4.55-4.52 (m,2H), 4.51 (s, 2H), 4.49 (s, 2H), 4.43-4.41 (m, 2H), 4.26 (s, 2H), 4.19(s, 2H), 3.76-3.70 (m, 1H), 3.61-3.54 (m, 1H), 2.49-2.47 (m, 2H),2.40-2.36 (m, 2H), 2.16-1.99 (m, 8H), 1.88-1.84 (m, 4H), 1.73-1.66 (m,4H), 1.62-1.58 (m, 4H), 1.37-1.16 (m, 8H), 2 OH signals and 2 NH signalsare not visible; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for HRMS (MALDI-TOF)m/z [M+Na]⁺ calcd for C₂₅H₃₁ClN₂O₆Na: 513.1769. found: 513.1788.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 11.20 (s, 1H), 11.00 (s, 1H), 6.62 (s,1H), 6.56 (s, 1H), 6.55 (d, J=15.7 Hz, 1H), 6.20-6.14 (m, 1H), 6.02 (dt,J=15.7, 7.32 Hz, 1H), 5.84 (d, J=16.4 Hz, 1H), 5.18-5.06 (m, 4H), 4.74(s, 2H), 4.58-4.55 (m, 4H), 4.44 (s, 2H), 4.26 (s, 2H), 4.22 (s, 2H),3.78 (s, 3H), 3.66 (s, 3H), 2.51-2.48 (m, 1H), 2.39-2.36 (m, 3H),2.32-2.29 (m, 1H), 2.26-2.24 (m, 1H), 2.14-2.06 (m, 4H), 2.00-1.99 (m,2H), 2 OH signals are not visible; HRMS (MALDI-TOF) m/z [M+Na]⁺ calcdfor HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₀H₂₂ClNO₇Na: 446.0983.found: 446.0975.

¹H NMR (CDCl₃, 400 MHz, 25° C.) δ 11.57 (s, 1H), 11.44 (s, 1H), 6.91 (d,J=16.1 Hz, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 6.27 (dt, J=16.1, 6.96 Hz,1H), 6.02 (dt, J=15.6, 6.44 Hz, 1H), 5.71-5.88 (m, 3H), 5.58-5.67 (m,1H), 5.50 (d, J=15.6 Hz, 1H), 4.99-5.15 (m, 6H), 4.84-4.91 (m, 2H), 4.80(s, 2H), 4.50 (s, 2H), 4.30-4.36 (dt×2, J=12.3, 6.48 Hz, 4H), 4.23 (s,2H), 4.19 (s, 2H), 3.23-3.58 (m, 8H), 2.38-2.48 (m, 4H), 2.31-2.37 (m,2H), 2.21-2.26 (m, 2H), 2.00-2.04 (m, 4H), 1.44-1.66 (m, 12H); HRMS(MALDI-TOF) m/z [M+Na]⁺ calcd for HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd forC₂₆H₃₃ClN₂O₆Na: 527.1925. found: 527.1906.

Mixture of isomers 3:1 in the oxime. Major isomer E: ¹H NMR (CDCl₃, 400MHz, 25° C.) δ 11.46 (bs, 1H), 6.63 (s, 1H), 6.03 (m, 1H), 5.30-5.05 (m,2H), 5.13 (d, J=16.1 Hz, 1H), 4.84 (s, 1H), 4.82 (s, 1H), 4.27 (s, 1H),4.15 (s, 1H), 3.65-3.40 (m, 4H), 3.34-3.21 (m, 1H), 2.65-1.92 (m, 6H),1.35-1.20 (m, 6H), 0.97 (t, J=7.3 Hz, 3H), 0.91 (q, J=7.3 Hz, 2H), 0.90(q, J=7.3 Hz, 2H).

Mixture of isomers 4:1 in the oxime. Major isomer E ¹H NMR (CDCl₃, 400MHz, 25° C.) δ 11.31 (s, 1H), 6.41 (s, 1H), 6.22 (m, 1H), 5.50 (d,J=15.8 Hz, 1H), 5.44-5.26 (m, 2H), 4.79 (s, 2H), 4.49 (t, J=5.6 Hz, 2H),4.21 (s, 2H), 3.62-3.37 (m, 4H), 2.33-1.93 (m, 8H), 1.34-1.21 (m, 4H),0.93-0.79 (m, 2H).

Mixture of isomers 3:1 in the oxime. Major isomer E ¹H NMR (CDCl₃, 400MHz, 25° C.) δ 12.07 (s, 1H), 6.56 (s, 1H), 6.20-5.88 (m, 1H), 6.03 (d,J=16 Hz, 1H), 5.60-5.46 (m, 1H), 4.92 (d, J=23.1 Hz, 2H), 4.53-4.44 (m,1H), 4.48 (s, 2H), 4.08 (s, 2H), 3.60-3.32 (m, 4H), 3.20 (m, 2H), 2.75(t, J=6.3 Hz, 2H), 2.50-2.39 (m, 2H), 2.28-2.15 (m, 2H), 1.37-1.23 (m,4H), 0.93-0.78 (m, 2H).

Mixture of isomers 3:1 in the oxime. Major isomer E ¹H NMR (CDCl₃, 400MHz, 25° C.) δ 10.58 (s, 1H), 6.64 (s, 1H), 6.22-6.15 (m, 1H), 5.41 (d,J=13.3 Hz, 1H), 5.31 (s, 2H), 5.27-5.13 (m, 2H), 4.61 (s, 2H), 4.03 (t,J=7 Hz, 2H), 3.63-3.37 (m, 4H), 2.56-2.02 (m, 6H), 1.38-1.22 (m, 4H),0.93-0.78 (m, 2H).

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.92(brs, 1H), 11.77 (brs, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.53 (d, J=2.4 Hz,1H), 6.36 (d, J=2.4 Hz, 1H), 6.35 (d, J=2.8 Hz, 1H), 5.43-5.17 (m, 6H),5.11 (s, 1H), 5.02 (s, 1H), 4.88 (d, J=14.4 Hz, 1H), 4.81-4.74 (m, 2H),4.70 (d, J=14.4 Hz, 1H), 4.46 (d, J=13.6 Hz, 1H), 4.16-4.09 (m, 2H),3.96 (d, J=15.6 Hz, 1H), 3.64-3.37 (m, 8H), 2.78-2.60 (m, 4H), 2.23-2.12(m, 8H), 1.79 (s, 3H), 1.65-1.56 (m, 12H), 1.53 (s, 3H), 1.35 (d, J=6.4Hz, 3H), 1.29 (d, J=6.4 Hz, 3H).

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 10.95(brs, 2H), 7.11 (d, J=2.4 Hz, 2H), 6.32 (d, J=2.4 Hz, 2H), 6.09-6.01 (m,2H), 5.95 (d, J=16.8 Hz, 2H), 5.91 (d, J=16.4 Hz, 2H), 5.76-5.68 (m,2H), 5.11 (s, 2H), 4.94 (s, 2H), 4.84 (s, 4H), 4.57 (t, J=5.2 Hz, 4H),4.26 (s, 4H), 3.59-3.53 (m, 4H), 3.39-3.33 (m, 4H), 2.67 (t, J=5.2 Hz,4H), 2.23-2.17 (m, 8H), 1.60-1.52 (m, 8H), 1.36-1.28 (m, 4H).

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.21(brs, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.62 (d, J=16.4 Hz, 1H), 6.30 (d,J=2.8 Hz, 1H), 6.23-6.15 (m, 1H), 5.52-5.44 (m, 1H), 5.40-5.31 (m, 1H),4.82 (d, J=14.8 Hz, 1H), 4.75 (d, J=14.8 Hz, 1H), 4.51 (d, J=14.8 Hz,1H), 4.21 (t, J=6.2 Hz, 1H), 3.66 (d, J=15.2 Hz, 1H), 3.44-3.35 (m, 2H),3.34-3.28 (m, 2H), 2.33-2.20 (m, 2H), 2.14-1.98 (m, 4H), 1.45 (d, J=6.8Hz, 3H), 1.14 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H). HRMS(MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₄H₃₂NaN₂O₆: 467.2158. found:467.2176.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.92(brs, 1H), 11.83 (brs, 1H), 6.98 (d, J=2.4 Hz, 2H), 6.34-6.33 (m, 2H),5.38-5.15 (m, 6H), 4.93 (d, J=14.4 Hz, 2H), 4.79-4.68 (m, 2H), 4.75 (d,J=14.4 Hz, 2H), 4.27 (d, J=14.4 Hz, 2H), 4.04 (d, J=14.4 Hz, 2H),3.44-3.26 (m, 8H), 2.24-2.19 (m, 4H), 1.74-1.72 (m, 14H), 1.36 (d, J=6.8Hz, 6H), 1.34 (d, J=6.8 Hz, 6H), 1.27-1.21 (m, 6H), 1.14 (t, J=7.4 Hz,6H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcd for C₂₅H₃₅N₂O₆: 459.2495. found:459.2499.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.70(brs, 1H), 11.69 (brs, 1H), 6.99 (brs, 1H), 6.72 (d, J=2.8 Hz, 1H), 6.64(d, J=16.4 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 6.31 (d, J=2.4 Hz, 1H),6.28-6.17 (m, 2H), 5.91 (d, J=16 Hz, 1H), 5.38-5.33 (m, 4H), 4.87 (s,2H), 4.79 (s, 2H), 4.57-4.53 (m, 4H), 4.34 (s, 2H), 4.07 (s, 2H),3.43-3.37 (m, 4H), 3.34-3.28 (q, J=7.2 Hz, 4H), 2.53-2.48 (m, 4H),2.16-1.97 (m, 8H), 1.29-1.24 (m, 12H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcdfor C₂₃H₃₁N₂O₆: 431.2182. found: 431.2186.

Mixture of isomers 7:1 in the oxime. Major isomer E ¹H NMR (CDCl₃, 400MHz) δ 11.82 (brs, 1H), 7.75 (brs, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.34 (d,J=2.4 Hz, 1H), 5.35-5.28 (m, 1H), 5.20 (s, 1H), 5.14-5.10 (m, 1H), 4.94(d, J=14.4 Hz, 1H), 4.74 (d, J=14.4 Hz, 1H), 4.31 (d, J=14.4 Hz, 1H),4.07 (d, J=14.4 Hz, 1H), 3.44-3.28 (m, 4H), 2.70-2.63 (m, 1H), 2.25-2.18(m, 2H), 2.14-2.07 (m, 2H), 1.73-1.72 (m, 6H), 1.25-1.21 (m, 6H), 1.14(t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H). HRMS (MALDI-TOF) m/z [M+Na]⁺calcd for C₂₇H₃₈NaN₂O₆: 509.2627. found: 509.2652.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.79(brs, 1H), 11.03 (brs, 1H), 6.61 (s, 1H), 6.08 (s, 1H), 5.42-5.28 (m,6H), 4.79 (d, J=13.2 Hz, 2H), 4.74 (d, J=13.6 Hz, 2H), 4.39 (m, 2H),4.27-4.23 (m, 3H), 3.61-3.54 (m, 4H), 3.51-3.45 (m, 4H), 2.53-2.47 (m,2H), 2.33-2.20 (m, 4H), 2.06-1.91 (m, 8H), 1.70-1.58 (m, 12H), 1.44-129(m, 13H), 0.95 (t, J=7.2 Hz, 6H). HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd forC₂₇H₃₇ClNaN₂O₆: 543.2237. found: 543.2263.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₃H₃₀NaN₂O₆: 453.2001. found:453.2010.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 6.99(brs, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.61 (d, J=16.8 Hz, 1H), 6.32 (d,J=2.4 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H), 6.25-6.10 (m, 2H), 5.89 (d,J=16.4 Hz, 1H), 5.50-5.31 (m, 4H), 4.94 (d, J=14.4 Hz, 2H), 4.84-4.76(m, 4H), 4.50 (d, J=15.2 Hz, 1H), 4.44 (d, J=14.4 Hz, 1H), 4.29 (d,J=14.4 Hz, 1H), 4.21 (t, J=6.0 Hz, 1H), 2.72-2.61 (m, 4H), 2.35-2.19 (m,6H), 2.15-1.96 (m, 8H), 1.93-1.82 (m, 3H), 1.38-1.28 (m, 11H), 0.96 (t,J=7.6 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcdfor C₂₇H₃₇N₂O₆: 485.2651. found: 485.2611.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₇H₃₈NaN₂O₆: 509.2628. found:509.2639.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 6.61 (s,1H), 6.05 (s, 1H), 5.41-5.26 (m, 6H), 4.80-4.75 (m, 3H), 4.58-4.47 (m,4H), 4.30-4.17 (m, 3H), 4.21 (t, 2H, J5.6 Hz), 4.05-4.01 (m, 2H),3.61-3.54 (m, 4H), 3.49-3.42 (m, 4H), 2.46-2.40 (m, 2H), 2.24-2.20 (m,3H), 2.07-1.90 (m, 8H), 1.34-1.28 (m, 15H). HRMS (MALDI-TOF) m/z [M+Na]⁺calcd for C₂₇H₃₁NaN₂O₆: 501.1768. found: 501.1718.

Mixture of isomers 5:1 in the oxime. Major isomer E ¹H NMR (CDCl₃, 400MHz) δ 11.85 (brs, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H),5.38-5.31 (m, 2H), 5.25 (s, 1H), 5.23-5.11 (m, 2H), 4.96 (d, J=14.4 Hz,1H), 4.74 (d, J=14.4 Hz, 1H), 4.34 (d, J=14 Hz, 1H), 4.21 (t, J=6 Hz,1H), 4.10 (d, J=14 Hz, 1H), 3.43-3.27 (m, 4H), 1.70 (s, 3H), 1.61-1.59(m, 4H), 1.37-1.29 (m, 7H), 1.13 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz,3H). HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₇H₃₈NaN₂O₆: 509.2627.found: 509.2680.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₆H₃₄NaN₂O₆: 493.2314. found:493.2331.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₈H₃₇ClNaN₂O₆: 555.2238. found:555.2242.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₅H₃₁ClNaN₂O₆: 513.1768. found:513.1780.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₆H₃₃ClNaN₂O₆: 527.1925. found:527.1939.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₄H₂₉ClNaN₂O₆: 499.1612. found:499.1626.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₆H₃₃ClNaN₂O₆: 527.1925. found:527.1932.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₅H₃₂NaN₂O₆: 479.2158. found:479.2174.

HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₆H₃₄NaN₂O₆: 493.2315. found:493.2319.

Mixture of isomers 4:1 in the oxime. Major isomer E ¹H NMR (CDCl₃, 400MHz) δ 7.40 (d, J=2.4 Hz, 1H), 6.31 (d, J=2.4 Hz, 1H), 6.19-6.11 (m,1H), 5.89 (d, J=16 Hz, 1H), 5.53-5.46 (m, 1H), 5.41-5.32 (m, 1H), 4.93(d, J=14.8 Hz, 1H), 4.81 (d, J=14.8 Hz, 1H), 4.44 (d, J=14.8 Hz, 1H),4.28 (d, J=14.8 Hz, 1H), 4.21 (t, J=5.6 Hz, 1H), 3.44-3.29 (m, 2H),2.35-2.20 (m, 2H), 2.13-2.01 (m, 2H), 1.45 (d, J=6.8 Hz, 3H), 1.37-1.28(m, 4H), 1.14 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.6H, 3H z). HRMS(MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₄H₃₂NaN₂O₆: 467.2158. found:467.2147.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.60(brs, 1H), 11.42 (brs, 1H), 7.35-7.28 (m, 9H), 6.69-6.62 (m, 2H), 6.49(d, J=16 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 6.32(d, J=2.4 Hz, 1H), 6.28-6.24 (m, 1H), 6.23 (d, J=2.8H, 1H), 6.10 (dt,J=16, 7.2 Hz, 1H), 5.73 (d, J=16 Hz, 1H), 5.36-5.31 (m, 2H), 5.27-5.18(m, 2H), 4.70 (s, 2H), 4.65 (s, 2H), 4.55-4.51 (m, 5H), 4.45 (t, J=5.3Hz, 2H), 4.27 (s, 2H), 4.08 (s, 2H), 2.50-2.42 (m, 4H), 2.17-2.07 (m,8H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcd for C₂₆H₂₉N₂O₆: 465.2025. found:465.1981.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.67(brs, 1H), 11.65 (brs, 1H), 8.00 (brs, 1H), 7.77 (brs, 1H), 7.13 (brs,1H), 6.63-6.59 (m, 2H), 6.32 (2d, J=2.8 Hz, 2H), 6.27-6.12 (m, 2H), 5.86(d, J=16.4 Hz, 1H), 5.37-5.33 (m, 4H), 4.95-4.72 (m, 4H), 4.57-4.51 (m,4H), 4.34 (s, 2H), 4.10 (d, J=15.2 Hz, 1H), 4.03 (d, J=15.2 Hz, 1H),3.58-3.48 (m, 2H), 3.20-3.09 (m, 2H), 2.77-2.69 (m, 2H), 2.53-2.45 (m,4H), 2.17-2.05 (m, 8H), 1.71-1.32 (m, 12H), 1.30-1.12 (m, 6H). HRMS(MALDI-TOF) m/z [M+H]⁺ calcd for C₂₅H₃₃N₂O₆: 457.2338. found: 457.2332.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.66(brs, 1H), 11.64 (brs, 1H), 7.56 (brs, 1H), 7.36 (brs, 1H), 6.95 (d,J=2.8 Hz, 1H), 6.59-6.54 (m, 2H), 6.33 (d, J=2.8 Hz, 1H), 6.32 (d, J=2.8Hz, 1H), 6.28-6.13 (m, 2H), 5.84 (d, J=16.1 Hz, 1H), 5.38-5.32 (m, 4H),4.85 (s, 2H), 4.78 (s, 2H), 4.54 (t, J=5.2 Hz, 4H), 4.33 (s, 2H), 4.07(s, 2H), 3.71-3.64 (m, 12H), 3.52-3.48 (m, 4H), 2.50 (brt, J=4.8 Hz,4H), 2.17-2.07 (m, 8H). HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd forC₂₃H₂₈NaN₂O₇: 467.1794. found: 467.1765.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.62(brs, 2H), 6.96 (d, J=2 Hz, 1H), 6.58 (d, J=2.8 Hz, 1H), 6.60 (d, J=2.8Hz, 1H), 6.32 (brd, J=2.4 Hz, 2H), 6.24-6.10 (m, 2H), 5.81 (d, J=16 Hz,1H), 5.35-5.32 (m, 3H), 4.92-4.72 (m, 4H), 4.56-4.45 (m, 4H), 4.31 (brs,2H), 4.04 (brs, 2H), 3.75-3.67 (m, 1H), 3.59-3.51 (m, 1H), 3.12-3.03 (m,1H), 2.64 (t, J=12.8 Hz, 1H), 2.52-2.46 (m, 4H), 2.14-2.04 (m, 8H),1.70-1.58 (m, 10H). HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₆H₃₄NaN₂O₆:493.2314. found: 493.2332.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.65(brs, 2H), 7.32-7.27 (m, 4H), 7.24-7.10 (m, 6H), 7.01 (d, J=2.4 Hz, 1H),6.64-6.59 (m, 2H), 6.34-6.33 (m, 2H), 6.28-6.18 (m, 2H), 5.85 (d, J=16Hz, 1H), 5.37-5.32 (m, 4H), 4.85 (s, 2H), 4.72-4.69 (m, 2H), 4.56-4.51(m, 4H), 4.15 (d, J=15.2 Hz, 2H), 4.02 (d, J=15.2 Hz, 2H), 3.96-3.92 (m,2H), 3.21-3.11 (m, 2H), 2.76-2.67 (m, 4H), 2.54-2.45 (m, 4H), 2.12-2.02(m, 10H), 1.90-1.87 (m, 4H), 1.67-1.58 (m, 4H). HRMS (MALDI-TOF) m/z[M+Na]⁺ calcd for C₃₀H₃₄NaN₂O₆: 541.2314. found: 541.2314.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.65(brs, 1H), 11.64 (brs, 1H), 8.70 (brs, 1H), 8.27 (brs, 1H), 7.04 (d,J=2.4 Hz, 1H), 6.64-6.60 (m, 2H), 6.26-6.11 (m, 2H), 6.32 (2d, J=2.6 Hz,2H), 5.82 (d, J=16 Hz, 1H), 5.36-5.32 (m, 4H), 4.76 (s, 2H), 4.70 (s,2H), 4.53 (brt, J=5.2 Hz, 4H), 4.33 (s, 2H), 4.05 (s, 2H), 3.51 (brt,J=6.8 Hz, 4H), 3.44 (q, 0.1=7.2 Hz, 4H), 2.52-2.46 (m, 4H), 2.16-2.05(m, 8H), 2.02-1.93 (m, 4H), 1.90-1.84 (m, 4H). HRMS (MALDI-TOF) m/z[M+H]⁺ calcd for C₂₃H₂₉N₂O₆: 429.2025. found: 429.2003.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.66(brs, 1H), 11.64 (brs, 1H), 8.15 (brs, 1H), 7.86 (brs, 1H), 7.31-7.27(m, 4H), 7.21-7.18 (m, 2H), 7.15-7.10 (m, 4H), 7.00 (brs, 1H), 6.60 (d,J=15.6 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.32 (2d, J=2.4 Hz, 2H),6.27-6.11 (m, 2H), 5.85 (d, J=16 Hz, 1H), 5.36-5.32 (m, 4H), 4.84 (s,2H), 4.77 (s, 2H), 4.59-4.48 (m, 4H), 4.33 (s, 2H), 4.11 (d, J=15.2 Hz,1H), 4.02 (d, J=15.6 Hz, 1H), 3.78-3.71 (m, 2H), 3.01-2.92 (m, 2H),2.59-2.47 (m, 8H), 2.12-2.07 (m, 8H), 1.82-1.68 (m, 6H), 1.36-1.30 (m,8H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcd for C₃₁H₃₇N₂O₆: 533.2651. found:533.2625.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.72(brs, 1H), 11.71 (brs, 1H), 6.71 (d, 1H, J2.4 Hz), 6.67 (d, 1H, J 16.4Hz), 6.35 (2d, 2H, J3 Hz), 6.31-6.18 (m, 2H), 5.93 (d, 1H, J 16.4 Hz),5.41-5.36 (m, 4H), 4.86 (s, 2H), 4.77 (s, 2H), 4.60-4.54 (m, 4H), 4.37(s, 2H), 4.10 (s, 2H), 3.94-3.86 (m, 2H), 3.62-3.49 (m, 2H), 2.55-2.49(m, 4H), 2.20-2.10 (m, 8H), 1.44-1.25 (m, 24H). HRMS (MALDI-TOF) m/z[M+H]⁺ calcd for C₂₅H₃₅N₂O₆: 459.2495. found: 459.2514.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.65(brs, 1H), 11.64 (brs, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.61-6.57 (m, 2H),6.33-6.32 (m, 2H), 6.25-6.10 (m, 2H), 5.82 (d, J=16 Hz, 1H), 5.36-5.31(m, 4H), 4.85 (s, 2H), 4.78 (s, 2H), 4.58-4.48 (m, 4H), 4.41-4.32 (m,4H), 4.12-3.98 (m, 2H), 3.72-3.58 (m, 2H), 3.02-2.93 (m, 1H), 2.72-2.62(m, 2H), 2.53-2.45 (m, 4H), 2.35-2.28 (m, 1H), 2.16-2.04 (m, 8H),1.86-1.39 (m, 8H), 1.17-1.07 (m, 2H), 0.93-0.88 (m, 6H). HRMS(MALDI-TOF) m/z [M+H]⁺ calcd for C₂₅H₃₃N₂O₆: 457.2338. found: 457.2380.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.67(brs, 2H), 6.99 (s, 1H), 6.68-6.63 (m, 2H), 6.32 (d, J=2.4 Hz, 1H), 6.31(d, J=2.8 Hz, 1H), 6.27-6.14 (m, 2H), 5.90 (d, J=16 Hz, 1H), 5.37-5.34(m, 4H), 4.77 (s, 2H), 4.63-4.46 (m, 4H), 4.36 (brs, 2H), 4.21 (t, J=6Hz, 4H), 4.05-3.92 (m, 4H), 2.55-2.46 (m, 4H), 2.17-2.06 (m, 8H),1.37-1.28 (m, 12H), 0.93-0.86 (m, 12H). HRMS (MALDI-TOF) m/z [M+Na]⁺calcd for C₂₆H₃₄NaN₂O₆: 493.2314. found: 493.2314.

Mixture of isomers 2:1 in the oxime. Major isomer E ¹H NMR (CDCl₃, 400MHz) δ 11.62 (brs, 1H), 6.98 (m, 1H), 6.57 (m, 2H), 6.32 (m, 2H), 6.18(m, 2H), 5.82 (d, J=15.6 Hz, 1H), 5.67 (m, 2H), 5.33 (m, 4H), 4.87 (d,J=13.6 Hz, 2H), 4.80 (d, J=10.8 Hz, 2H), 4.53 (m, 3H), 4.33 (s, 2H),4.05 (brs, 4H), 3.73 (m, 2H), 3.69 (q, J=6 Hz, 2H), 3.52 (q, J=5.2 Hz,2H), 2.48 (m, 5H), 2.13 (m, 13H). HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd forC₂₄H₂₈NaN₂O₆: 463.1845. found: 463.1870.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.66(brs, 1H), 11.64 (brs, 1H), 8.29 (brs, 2H), 6.89 (d, J=2.8 Hz, 1H), 6.59(d, J=16H, 1H z), 6.57 (d, J=2.4 Hz, 1H), 6.33-6.32 (m, 2H), 6.24-6.09(m, 2H), 5.79 (d, J=16 Hz, 1H), 5.34-5.30 (m, 4H), 4.85 (s, 2H), 4.78(s, 2H), 4.56-4.48 (m, 4H), 4.31 (s, 2H), 4.10 (d, J=15.6 Hz, 1H), 4.05(d, J=15.6 Hz, 1H), 3.80-3.71 (m, 2H), 3.06-2.96 (m, 2H), 2.61 (dt,J=12.8, 2.6 Hz, 2H), 2.52-2.46 (m, 4H), 2.16-2.05 (m, 8H), 1.71-1.58 (m,6H), 1.17-1.05 (m, 4H), 0.94 (d, J=5.6 Hz, 3H), 0.93 0.94 (d, J=5.6 Hz,3H). HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₅H₃₂ NaN₂O₆: 479.2158.found: 479.2182.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.60(brs, 1H), 11.47 (brs, 1H), 8.58 (brs, 2H), 6.53 (d, J=16.4 Hz, 1H),6.50 (d, J=2.4 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H),6.30 (d, J=2.4 Hz, 1H), 6.31-6.27 (m, 2H), 6.14 (m, 1H), 5.39-5.31 (m,4H), 4.61 (s, 2H), 4.56-4.53 (m, 6H), 4.33 (s, 2H), 4.09 (s, 2H),3.86-3.75 (m, 2H), 2.53-2.48 (m, 4H), 2.17-2.09 (m, 8H), 1.93-1.86 (m,4H), 1.70-1.55 (m, 8H), 1.39-1.11 (m, 8H). HRMS (MALDI-TOF) m/z [M+Na]⁺calcd for C₂₅H₃₂NaN₂O₆: 479.2158. found: 479.2157.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.65(brs, 2H), 7.06 (d, J=2.4 Hz, 1H), 6.62-6.57 (m, 2H), 6.33 (d, J=2.4 Hz,2H), 6.21-6.11 (m, 2H), 5.81 (d, J=16.4 Hz, 1H), 5.37-5.29 (m, 4H), 4.86(s, 2H), 4.79 (s, 2H), 4.52 (brt, J=5.2 Hz, 4H), 4.31 (s, 2H), 4.02 (s,2H), 3.21 (m, 4H), 3.09 (dd, J=10.8, 8.0 Hz, 4H), 2.52-2.44 (m, 4H),2.11-1.91 (m, 12H), 0.95 (d, J=6.8 Hz, 6H), 0.93 (d, J=6.8 Hz, 6H), 0.88(d, J=6.8 Hz, 6H), 0.86 (d, J=6.8 Hz, 6H). HRMS (MALDI-TOF) m/z [M+Na]⁺calcd for C₂₇H₃₈NaN₂O₆: 509.2627. found: 509.2626.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.67(brs, 1H), 11.66 (brs, 1H), 7.38-7.28 (m, 12H), 7.22-7.14 (m, 8H), 6.94(d, J=2.4 Hz, 1H), 6.57-6.53 (m, 2H), 6.33 (brd, J=2.4 Hz, 2H),6.22-6.12 (m, 2H), 5.85 (d, J=16 Hz, 1H), 5.35-5.32 (m, 4H), 4.93 (s,2H), 4.86 (s, 2H), 4.62 (s, 2H), 4.60 (s, 2H), 4.53 (brt, J=5.2 Hz, 4H),4.46 (s, 2H), 4.43 (s, 2H), 4.30 (s, 2H), 4.07 (s, 2H), 3.52-3.46 (m,4H), 2.16-2.07 (m, 8H). HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd forC₃₃H₃₄NaN₂O₆: 577.2314. found: 577.2278.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.66(brs, 1H), 11.65 (brs, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.62-6.55 (m, 2H),6.32-6.29 (m, 2H), 6.23-6.11 (m, 2H), 5.82 (d, J=16 Hz, 1H), 5.34-5.29(m, 4H), 4.85 (s, 2H), 4.77 (s, 2H), 4.54 (brt, J=5.2 Hz, 4H), 4.32 (s,2H), 4.04 (s, 2H), 3.32-3.27 (m, 4H), 3.21-3.15 (m, 4H), 2.52-2.42 (m,4H), 2.10-2.04 (m, 8H), 1.67-1.51 (m, 8H), 0.96-0.86 (m, 12H). HRMS(MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₅H₃₄NaN₂O₆: 481.2314. found:481.2307.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.63(brs, 2H), 6.88 (d, J=2.0 Hz, 1H), 6.55 (d, J=16.4 Hz, 1H), 6.43 (d,J=2.4 Hz, 1H), 6.32 (d, J=2.4 Hz 1H), 6.30 (d, J=2 Hz, 1H), 6.28-6.13(m, 2H), 5.84 (d, J=16.1 Hz, 1H), 5.36-5.33 (m, 4H), 4.82 (s, 2H), 4.73(s, 2H), 4.54 (t, J=5.5 Hz, 4H), 4.32 (s, 2H), 4.09 (s, 2H), 3.91-3.85(m, 4H), 3.79-3.70 (m, 4H), 2.65-2.60 (m, 8H), 2.49 (brt, J=5.1 Hz, 4H),2.17-2.04 (m, 8H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcd for C₂₃H₂₈N₂O₆:461.1746. found: 461.1765.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.64(brs, 2H), 6.98 (d, J=2.3 Hz, 1H), 6.61 (d, J=16.3 Hz, 1H), 6.58 (d,J=2.4 Hz, 1H), 6.31 (2d, J=2.2 Hz, 2H), 6.27-6.12 (m, 2H), 5.87-5.78 (m,5H), 5.45-5.33 (m, 4H), 4.74 (s, 2H), 4.69 (s, 2H), 4.53 (t, J=5.3 Hz,4H), 4.33 (s, 2H), 4.28-4.25 (m, 8H), 4.05 (s, 2H), 2.52-2.46 (m, 4H),2.17-2.05 (m, 8H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcd for C₂₃H₂₇N₂O₆:427.1869. found: 427.1902.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.68(brs, 2H), 7.16 (d, J=2.8 Hz, 1H), 6.63 (d, J=16.3 Hz, 1H), 6.60 (d,J=2.0 Hz, 1H), 6.31 (brs, 2H), 6.26-6.13 (m, 2H), 5.85 (d, J=16.0 Hz,1H), 5.77-5.76 (m, 4H), 5.44-5.34 (m, 4H), 4.87-4.59 (m, 10H), 4.48-4.43(m, 2H), 4.33 (brs, 2H), 4.19 (d, J=15.3 Hz, 1H), 3.91 (d, J=15.3 Hz,1H), 2.54-2.44 (m, 4H), 2.19-2.05 (m, 8H), 1.36-1.30 (m, 12H). HRMS(MALDI-TOF) m/z [M+H]⁺ calcd for C₂₅H₃₁N₂O₆: 455.2182. found: 455.2195.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.66(brs, 1H), 11.63 (brs, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.57 (d, J=16.0 Hz,1H), 6.52 (d, J=2.4 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 6.31 (d, J=2.4 Hz,1H), 6.29-6.12 (m, 2H), 5.84 (d, J=16.0 Hz, 1H), 5.38-5.32 (m, 4H),4.91-4.71 (m, 4H), 4.59-4.49 (m, 4H), 4.37-4.26 (m, 4H), 4.13-3.97 (m,4H), 3.78-3.68 (m, 2H), 3.62-3.52 (m, 2H), 3.35-3.15 (m, 4H), 2.50 (brt,J=5.2 Hz, 4H), 2.18-2.08 (m, 8H), 1.24-1.18 (m, 12H). HRMS (MALDI-TOF)m/z [M+Na]⁺ calcd for C₂₅H₃₂NaN₂O₇: 495.2107. found: 495.2067.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.65(brs, 1H), 11.64 (brs, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.57 (d, J=16.4 Hz,1H), 6.52 (d, J=2.4 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 6.31 (d, J=2.4 Hz,1H), 6.28-6.13 (m, 2H), 5.84 (d, J=16 Hz, 1H), 5.38-5.31 (m, 4H), 4.86(s, 2H), 4.77 (s, 2H), 4.56-4.52 (m, 4H), 4.34 (s, 2H), 4.07 (s, 2H),3.61-3.45 (m, 16H), 2.54-2.46 (m, 4H), 2.16-2.05 (m, 8H), 1.47 (s, 18H).HRMS (MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₈H₃₇NaN₃O₈: 566.2478. found:566.2459.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.70(brs, 1H), 11.68 (brs, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.61 (d, J=16.4 Hz,1H), 6.53 (d, J=2.4 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H), 6.32 (d, J=2.4 Hz,1H), 6.28-6.13 (m, 2H), 5.86 (d, J=16.4 Hz, 1H), 5.38-5.33 (m, 4H), 4.75(s, 2H), 4.68 (s, 2H), 4.57-4.54 (m, 4H), 4.36 (s, 2H), 4.08 (s, 2H),3.79 (2s, 6H), 2.54-2.48 (m, 4H), 2.17-2.04 (m, 8H).

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 6.94 (d,J=2.4 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.34 (d, J=2.8 Hz, 1H), 6.32 (d,J=2.0 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 6.25-6.12 (m, 2H), 5.86 (d,J=16.0 Hz, 1H), 5.38-5.32 (m, 4H), 4.85 (s, 2H), 4.71 (s, 2H), 4.57-4.52(m, 4H), 4.35 (s, 2H), 4.14 (s, 2H), 3.73-3.58 (m, 8H), 3.02-2.87 (m,8H), 2.54-2.48 (m, 4H), 2.14-2.09 (m, 8H). HRMS (MALDI-TOF) m/z [M+Na]⁺calcd for C₂₃H₂₉NaN₃O₆: 466.1954. found: 466.1938.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.94(brs, 1H), 11.80 (brs, 1H), 6.80 (d, J=2.4 Hz, 2H), 6.35 (d, J=2.4 Hz,2H), 5.45-5.09 (m, 6H), 4.93 (d, J=14.4 Hz, 2H), 4.82-4.68 (m, 2H), 4.76(d, J=14.4 Hz, 2H), 4.28 (d, J=14.8 Hz, 2H), 4.06 (d, J=14.4 Hz, 2H),3.63-3.33 (m, 8H), 2.34-1.96 (m, 10H), 1.70-1.55 (m, 12H), 1.45-1.29 (m,10H), 1.75 (s, 3H), 1.25 (s, 3H), 0.94 (t, J=7.2 Hz, 6H). HRMS(MALDI-TOF) m/z [M+Na]⁺ calcd for C₂₈H₃₈NaN₂O₆: 521.2627. found:521.2630.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.92(brs, 1H), 11.84 (brs, 1H), 7.08-7.05 (m, 2H), 6.35-6.33 (m, 2H),5.50-5.20 (m, 6H), 4.87 (s, 2H), 4.73 (s, 2H), 4.44-4.35 (m, 4H), 3.92(s, 2H), 3.60-3.49 (m, 4H), 3.44-3.33 (m, 4H), 2.47-2.38 (m, 4H),2.21-1.99 (m, 8H), 1.81-1.76 (m, 6H), 1.70-1.62 (m, 14H). HRMS(MALDI-TOF) m/z [M+H]⁺ calcd for C₂₅H₃₃N₂O₆: 457.2338. found: 457.2339.

Mixture of isomers 1:1 in the oxime. ¹H NMR (CDCl₃, 400 MHz) δ 11.61(brs, 1H), 11.57 (brs, 1H), 7.86 (brs, 1H), 7.64 (brs, 1H), 7.00 (d,J=2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 6.34 (brd, J=2.0 Hz, 2H),5.46-5.32 (m, 4H), 5.28-5.22 (m, 2H), 4.90 (d, J=14.8 Hz, 1H), 4.83 (d,J=14.4 Hz, 1H), 4.72 (d, J=14.4 Hz, 1H), 4.71 (d, J=14.8 Hz, 1H), 4.35(d, J=16.0 Hz, 1H), 4.25-4.17 (m, 3H), 4.09 (d, J=15.2 Hz, 1H),3.62-3.51 (m, 4H), 3.43-3.38 (m, 4H), 2.67-2.61 (m, 2H), 2.35-2.28 (m,2H), 2.06-1.95 (m, 4H), 1.90-1.78 (m, 6H), 1.68-1.58 (m, 14H), 1.44-1.31(m, 11H), 0.94 (m, 6H). HRMS (MALDI-TOF) m/z [M+H]⁺ calcd forC₂₇H₃₉N₂O₆: 487.2808. found: 487.2806.

¹H (E-isomer, MeOD, 400 MHz, 25° C.) δ 6.26 (d, J=2.4 Hz, 1H); 6.24 (d,J=2.4 Hz, 1H); 6.05 (d, J=16.4 Hz, 1H); 5.86-5.93 (m, 1H); 5.60-5.67 (m,1H); 5.44-5.50 (dt, 1H); 5.20-5.31 (m, 1H); 4.88 (dd, 2H); 4.44 (d, 1H);3.95-4.01 (m, 1H); 3.53-3.67 (m, 4H); 3.45 (d, 1H); 2.58 (dd, 1H);2.40-2.48 (m, 2H); 2.20 (dd, 1H); 1.64-1.76 (m, 6H); 1.48 (d, 3H). ¹³C(MeOD, 100 MHz, 25° C.) δ 170.4, 169.6, 169.3 (×2), 161.6 (×2), 159.5,159.4, 156.7, 140.7, 139.8, 139.4, 136.9, 136.8, 135.8, 129.4, 129.3,127.8, 121.1, 108.3, 108.1, 102.2, 102.1, 93.4, 73.8, 73.7, 72.8, 72.7,72.6, 72.4, 72.3, 47.3, 47.2, 47.0, 44.6, 44.2, 44.1, 41.5, 41.0, 40.4,40.1, 35.8, 29.7, 27.4, 27.3, 26.7, 26.6, 25.4, 24.4, 20.4, 20.2

HRMS (MALDI-TOF) m/z [M+H]⁺ calcd for C₂₆H₃₄N₅O₆: 512.2431. found:512.2406.

Example 6: Derivitization of Hydroxy-Substituted Macrocycles

The preparation of compounds of the invention that contain hydroxysubstituents on the macrocycle may be prepared from Weinreb amidessubstituted with a protected hydroxy group or by oxidation of the finalmacrocycle, as depicted in Scheme 9 above. Macrocycles containinghydroxy substituents may be derivatized by reagents that are reactive tohydroxy groups to produce macrocycles substituted with varying groups onthe macrocyclic ring. The use of orthogonal protecting groups on Weinrebamide precursors allows the selective liberation and reaction ofmacrocycle hydroxy groups.

In one non-limiting embodiment of the invention, macrocycles containinghydroxy substituents may be alkylated with electrophiles to producemacrocycles substituted with varying groups on the macrocyclic ring.

Deprotection of Hydroxy Group

A solution of the totally protected compound (140 mg, 0.2 mmol) in THF(3 mL) was treated with the solution of TBAF in THF (0.3 mL, 1M in THF,1.5 equiv.) at 0° C. The reaction was allowed to warm to 23° C. and foranother 3 hrs. The reaction was extracted from sat. NH₄Cl solution withethyl acetate (10 mL×3), washed by brine (15 mL), dried over anhydrousNa₂SO₄, and concentrated. Flash chromatography column (EA as eluent)gave desired compound (104 mg) in the yield of 88%.

Reaction with α-Halo Carbonyl Groups

To a solution of the free alcohol (50 mg, 0.085 mmol) in THF (0.6 mL) at0° C. under nitrogen atmosphere, NaH (20 mg, 0.5 mmol, 5.8 equiv.) wasadded and the reaction kept stirring for another half hour. Then Bu₄NI(10 mg, 0.027 mmol, 0.3 equiv) and chloride (79 mg, 0.51 mmol, 6.0equiv.) was added sequentially at the same temperature. The reaction waswarmed up slowly, heated to 60° C. overnight. The mixture was extractedfrom sat. NH₄Cl and ethyl acetate, and the organic phases were combined,washed by brine, dried over anhydrous Na₂SO₄, and concentrated. Flashchromatography (PE/EA, 1/2, EA, then EA/MeOH, 20:1) afforded the desiredcompound (36 mg). The solution of the compound previously obtained (36mg, 0.05 mmol) in MeOH (5 mL) was treated with sulfonic acid resin (83mg, 3 mmol/g, 5.0 equiv.) at 40° C. After stirring for 2 hours, thereaction was diluted with CH₂Cl₂ (5 mL), filtered, rinsed with MeOH andCH₂Cl₂. The filtrate was concentrated and underwent reverse phase column(CH₃CN/H₂O, 10%, 20%, 30%) to give the desired compound (19 mg). HRMS(MALDI-TOF) m/z [M+H]⁺ calcd for C₃₁H₄₁N₃O₉: 600.2921. found: 600.2919.

Reaction with Alkyl Halides and Formation of Azido-SubstitutedMacrocycles

To the solution of the free alcohol (20 mg, 0.034 mmol) in THF (0.5 mL)at 0° C. under nitrogen atmosphere, NaH (9.8 mg, 0.24 mmol, 7.2 equiv.)was added and the reaction kept stirring for another half hour. ThenBu₄NI (13 mg, 0.038 mmol, 1.1 equiv) and bromide (35 mg, 0.16 mmol, 4.7equiv.) was added sequentially at the same temperature. The reaction waswarmed up slowly and then heated to 23° C. for 4 hrs. The mixture wasextracted from sat. NH₄Cl and ethyl acetate, and the organic phases werecombined, washed by brine, dried over anhydrous Na₂SO₄, andconcentrated. The residue obtained was submitted to the next stepwithout further purification. To a solution of the crude mixtureobtained previously in DMSO (0.8 mL) was added NaN₃ (35 mg) at 60° C.and stirred for 2 hrs. The reaction was extracted from sat. NH₄Cl andethyl acetate and the organic phases were combined, washed by brine,dried over anhydrous Na₂SO₄, and concentrated. The residue underwentflash chromatography (PE/EA, 1/1) to give the desired compound (4 mg).The solution of this compound (4 mg, 0.006 mmol) in MeOH (1 mL) wastreated with sulfonic acid resin (20 mg, 3 mmol/g, 10.0 equiv.) at 40°C. After stirring for 4 hours, the reaction was diluted with CH₂Cl₂ (2mL), filtered, rinsed with MeOH and CH₂Cl₂. The filtrate wasconcentrated and preparative TLC (Hex/EA, 1/2) gave the desired compound(point 1, 4.5 mg, point 2, 1.3 mg). HRMS (MALDI-TOF) m/z [M+H]⁺ calcdfor C₂₈H₃₈N₅O₇: 556.2771. found: 556.2745.

Amino-Substituted Macrocycles and Derivatives

To the solution of the azide (30 mg, 0.044) in THF/H₂O (0.9/0.1 mL) wasadded triphenyl phosphine (23 mg, 0.088 mmol, 2 equiv.) at 40° C. andthe reaction was stirred for 1d. After evaporation to get rid of thesolvent, the residue underwent flash chromatography (PE/EA, 1/1 thenMeOH/NEt₃, 20/1) to afford the desired amine. To a solution of the amine(8 mg, 0.012 mmol) in DMF (2 mL) was added 2,6-lutidine (5 drops) andAc₂O sequentially at 0° C. under nitrogen atmosphere and the reactionwas warmed up to 23° C. and kept stirring for 1 hour. The mixture wasextracted from sat. NH₄Cl and ethyl acetate, and the organic phases werecombined, washed by brine, dried over anhydrous Na₂SO₄, andconcentrated. The residue obtained was submitted to the next stepwithout further purification. The solution of the crude compoundobtained in MeOH (1 mL) was treated with sulfonic acid resin (30 mg, 3mmol/g) at 40° C. After stirring for 1 hour, the reaction was filtered,rinsed with MeOH and CH₂Cl₂. The filtrate was concentrated andpreparative TLC (EA/MeOH, 10/1) gave the desired compound (1.9 mg). HRMS(MALDI-TOF) m/z [M+H]⁺ calcd for C₃₀H₄₂N₃O₈: 572.2972. found: 572.2940.

To the solution of the amine (11 mg, 0.017 mmol) in DMF (1 mL) was addedTNTU (10 mg, 1.35 equiv.), Hunig's base (20 μL, 3.0 equiv.), andfluorophore (15 mg, 1.5 equiv.) sequentially at 0° C. under nitrogenatmosphere and the reaction was warmed up to 23° C. and kept stirringfor 1 hour. The reaction was concentrated, and the residue underwentflash chromatography (PE/EA, 1/2, then CH₂Cl₂/MeOH, 10/1) to give theprotected compound. The solution of the Cy3 labeled protected compoundin MeOH (2 mL) was treated with sulfonic acid resin (30 mg, 3 mmol/g) at40° C. After stirring for 2 hours, the reaction was filtered, rinsedwith MeOH and DCM. The filtrate was concentrated and preparative TLC(CH₂Cl₂/MeOH, 10/1) gave the desired deprotected Cy3 labeled compound.MS (ES) m/z [M]⁺ calcd for C₅₇H₇₂N₅O₈: 954.54. found: 954.53.

Example 7: Alternate Synthesis of Hydroxy-Substituted Macrocycles

In addition to use of hydroxy-substituted Weinreb amides for thepreparation of hydroxy substituted macrocycles, hydroxy groups may beintroduced into the macrocycle by the mild allylic oxidation of thecompounds, as depicted in Scheme 9 and described below.

To a solution of bis protected macrocycle (100 mg, 0.17 mmol) in EtOH (1mL) was added selenium dioxide (56 mg, 0.51 mmol, 3.0 equiv.). Thereaction underwent microwave reaction at 110° C. for 2 h. Then themixture was filtered and the filtrate concentrated, flash chromatography(PE/EA, 1/1, 1/2, 1/4) gave the desired compound as a mixture of isomers(70 mg). To a solution of the previously obtained mixture (15 mg, 0.025mmol) in DMF (1.5 mL) at 0° C. under nitrogen atmosphere, NaH (6 mg,0.15 mmol, 9.0 equiv.) was added and the reaction kept stirring foranother half hour. Then Bu₄NI (10 mg, 0.027 mmol, 1.1 equiv) and allylchloride (50 μL, 20 equiv.) was added sequentially at the sametemperature. The reaction was warmed up to 23° C. and stirred for 1hour. The mixture was extracted from sat. NH₄Cl and ethyl acetate, andthe organic phases were combined, washed by brine, dried over anhydrousNa₂SO₄, and concentrated. Flash chromatography (PE/EA, 3/1) afforded thedesired compound (6 mg). A solution of the allylated alcohol (6 mg,0.009 mmol) in MeOH (1 mL) was treated with sulfonic acid resin (20 mg,3 mmol/g, 6.7 equiv.) at 40° C. After stirring for 2 hours, the reactionwas diluted with CH₂Cl₂ (3 mL), filtered, rinsed with MeOH and CH₂Cl₂.The filtrate was concentrated and underwent preparative TLC (Hex/EA,1/2) to give the desired compound.

Example 8: Additional Azide Derivatives

The azide containing macrocycle may be modified to produceamino-substituted compounds and derivatives thereof, similarly toExample 6 above.

To a solution of the azide analog (280 mg, 0,424 mmol, 1 eq.) in THF/H₂O(9/1) mixture (42 mL) was added PPh₃ (333.6 mg, 1,272 mmol, 3 eq.). Theresulting mixture was stirred overnight at 40° C. Then, the solution wasevaporated to dryness without any work-up. The crude was purified onsilica chromatography (CH₂Cl₂/MeOH=20/1) to yield the correspondingamine as a white solid (232.6 mg, 0,366 mmol, 86%). HRMS (MALDI-TOF) m/z[M+H]⁺ calcd for C₃₂H₄₇ClN₃O₈: 636.3052. found: 636.3071.

A solution of TNTU (8.52 mg, 23.3 μmol, 1.35 eq.), DIPEA (8.6 μL, 51.9μmol, 3 eq.) and Cy3 (14.8 mg, 25.9 μmol, 1.5 eq.) in dry NMP (0.3 mL)was shaken 45 min at room temperature. Then, the pre-activated acid wasadded to a solution of the previous amine (11 mg, 17.3 mmol, 1 eq.) in0.3 mL of NMP. After 12 hours the reaction mixture was diluted withAcOEt, washed with water (2 mL), KOH 2N (3 mL), dried with Na₂SO₄, andevaporated to dryness. The crude was purified on silica chromatography(CH₂Cl₂/MeOH=8/1) to yield the corresponding Cy3 labeled compound as apink solid (20 mg, quantitative). MS (ES) m/z [M]⁺ calcd forC₆₁H₇₉ClN₅O₉: 1061.56. found: 1061.25.

Example 9: Biological Activity

Compounds of the invention were assayed for cytotoxicity in HCC1954 andSK-BR-3 tumor cells. Compounds that showed significant cytotoxicity werefurther examined for their ability to induce degradation of known HSP90client proteins, such as ErbB2 in SK-BR3. Thus, after 18 hrs treatmentwith the compounds, the whole cell protein lysates were obtained,protein concentrations were normalized and the concentration of ErbB2was quantified by Western blotting (C. Chavany et al J. Biol. Chem.271:4974-4977 (1996)). Several compounds from the library were moreeffective than radicicol and 17-AAG in reducing ErbB2 concentration. Forexample compounds 13a, 13b and 13c in the form of the E-oxime isomerwere significantly more effective than both radicicol and 17-AAG.

A number of the compounds of the invention were tested for affinity toHSP90α (see Kim et al., J. Biomol. Screen., 2004, 9, 375), Her-2 (HSP90client) degradation (see Xu et al., J. Biol. Chem., 2001, 276, 3702),and cytotoxicity against SKBr3 and HCC1954, two breast cancer cell lineswhich over express Her-2. The results of the affinity to HSP90a, Her-2degradation and cytotoxicity are shown in Table 3.

TABLE 3 Biological Activity HSP90 Client affinity Depletion CytotoxicityCompd. (μM) (μM) (μM) radicicol 0.140 0.45 pochonin D 0.36 3.5 17-AAG0.032 0.050  13a 0.021 0.035 0.125; 0.320  13b 0.015 0.050 0.120; 0.220 13c 0.018 0.026 0.450; 0.630  13d 0.220 >10 >10; >10 13e >10 >10 >10; >10  13f 0.068 2.4 1.3; 2.8  13g 0.081 nt nt  13h0.390 7.7  7.5; >10  13i 1.20 nt >10; >10  13j 0.11 5.5 3.5; 8.5  13k0.090 0.25 0.55; 0.45  13l 0.190 6.5 >10; >10  13m >10 >10 >10; >10  14a1.8 >10 >10; 5.2   14b 0.110 5.0 >10; >10 336 <0.052 nt 349 0.046 0.105350 0.196 0.805 351 0.204 0.900 352 0.543 4.270 353 3.027 >10 354-E0.543 2.960 354-Z 0.601 4.110 356 0.511 9.480 357 0.196 0.730 3580.587 >10 359 1.936 >8.8 361 0.543 2.960 362 4.663 >10 363 0.900 >10 3651.751 8.970 366 0.170 2.040 367 1.723 >10 368 0.599 >10 369 0.154 0.677370 0.038 0.097 371 0.243 0.629 372 0.886 3.069 373 0.059 0.089 3740.238 2.030 375 0.070 0.201 376 2.240 >10 377 5.757 >10 378 0.057 0.929379 0.162 0.627 380 0.124 0.588 381 2.992 >10 382 0.022 0.122 383 0.1160.708 384 0.070 0.512 385 0.373 8.160 386 0.128 0.669 387 0.118 0.568388 0.219 0.509 389 0.155 0.454 390 0.094 0.549 391 0.337 2.830 3920.327 2.870 393 0.097 nt 394 0.096 1.580 395 0.097 0.754 396 0.182 3.650397 0.432 0.980 457 0.012 nt

Based on the in vitro data shown in Table 3, compound 13a was furtherevaluated in vivo. Treatment of CB17/SCID mice with compound 13a at 100mg/kg for five consecutive days was well tolerated with minimal weightloss observed. To investigate the in vivo efficacy of compound 13a, axenograft bearing BT-474 (breast tumor cell line) was used, as this cellline has been shown to respond to HSP90 inhibitors in an animal model(Basso et al., Oncogene 2002, 21, 1159). Based on the cellular potencyof compound 13a, two schedules of 100 mg every other day (q2d) or everyfour days (q4d) during 28 days were investigated. The treatment withcompound 13a resulted in a dose-dependent inhibition of the tumor growthwith an 18% regression in tumor volume using the q2d schedule. Theresults are shown in FIG. 1. Neither the q2d nor the q4d schedulesresulted in significant weight loss, which is illustrated in FIG. 2.Histologic examination of tumors removed from animals receiving eitherthe vehicle (DMSO) or drug for 28 days following the q2d schedulerevealed a dramatic loss of cellularity in tumors obtained fromdrug-treated animals. Nuclei of remaining cells were uniformlycondensed, suggesting the occurrence of massive apoptosis (see FIG. 4,top panels). This was confirmed by the high degree of nuclear TUNELstaining seen in tumors excised from drug treated animals, which isshown in FIG. 4, bottom panels. These data suggest that tumor regressionin animals treated for 28 days according to the q2d schedule may be moredramatic than estimated with tumor volume measurements, since few to noviable cells could be identified at the end of the treatment period.

The description and examples provided herein are merely illustrative,and the invention is not so limited. Numerous variations, permutationsand derivatives of these compounds, procedures and uses will occur tothose of ordinary skill in the art, and are contemplated within thescope of the invention.

What is claimed is:
 1. A compound of formula II or II′, or a tautomer thereof, a pharmaceutically acceptable salt, solvate, ester or prodrug thereof:

wherein: X is O, S or NR; Y is —OR, —O—(CH₂)_(m)COOR, —O—(CH₂)_(m)CON(R)₂, —N(R)₂, —N(R)SOR or —N(R)SO₂R, wherein the groups bound to the nitrogen atom may be in Z- or E-configuration; R¹ and R² are independently hydrogen, halogen, OR, N(R)₂, SR, azido, nitro, cyano, aliphatic, aryl, alkylaryl, arylalkyl, heterocyclyl, heteroaryl, —S(O)R, —S(O)₂R, —SO₂N(R)₂, —N(R)SO₂R, —N(CO)R, —N(CO)N(R)₂, —N(CO)OR, —O(CO)R, —(CO)R, —(CO)OR, —(CO)N(R)₂, —O(CO)OR, or —O(CO)N(R)₂; R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, halogen, azido, nitro, cyano, aliphatic, alkylaryl, aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)₂, SR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —O(CH₂)_(m)OC(O)(CH₂)_(p)R, —O(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —O(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —O(CH₂)_(m)OC(O)(CH₂)_(p)OR, —O(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)R, —NR(CH₂)_(m)OC(O) (CH₂)_(p)R, —NR(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —NR(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —NR(CH₂)_(m)OC(O)(CH₂)_(p)OR, —NR(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N(R)C(O) CH₂)_(p)R, —(CH₂)_(m)OC(O)(CH₂)_(p)R, —(CH₂)_(m)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)OR, —(CH₂)_(m)N(R)C(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)OC(O)(CH₂)_(p)OR, —(CH₂)_(m)OC(O)(CH₂)_(p)N(R)₂, —(CH₂)_(m)N₃, —O(CH₂)_(m)N₃—(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —(CH₂)_(m)S(O)(CH₂)_(p)R, —(CH₂)_(m)S(O)₂(CH₂)_(p)R, —(CH₂)_(m)SO₂(CH₂)_(p)N(R)₂, or —(CH₂)_(m)N(R)SO₂(CH₂)_(p)R; and each R is independently R¹¹, hydrogen, aliphatic, amino, azido, cyano, nitro, alkylamino, dialkylamino, OH, alkoxy, carbonylamino, aminocarbonyl, alkoxycarbonyl, carbonyloxy, carboxy, acyl, aryl, alkaryl, arylalkyl including benzyl, heteroalkyl, heteroaryl, heterocyclyl, or a protecting group; or two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclic or heteroaryl ring; wherein where a group contains more than one R substituent; wherein R is optionally substituted, and each R can be the same or different; R¹¹ is the group:

where Z is an inorganic or organic counterion; m and p are independently 0, 1, 2, 3, 4 or 5; wherein in formula II′, when X is O, then at least one of R⁵, R⁶, R⁷, R⁸, R⁹ or R¹⁰ is not hydrogen; and provided that when Y is —OR, R is not H.
 2. The compound of claim 1, wherein X is O or NR.
 3. The compound of claim 1, wherein X is O or NR; and Y is —OR, —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂.
 4. The compound of claim 1, wherein R¹ and R² are independently hydrogen or halogen.
 5. The compound of claim 1, wherein R³ and R⁴ are independently alkyl or hydrogen.
 6. The compound of claim 1, wherein, R⁹ and R¹⁰ are independently hydrogen or aliphatic.
 7. The compound of claim 1, wherein X is O; Y is —O—(CH₂)_(m)COOR or —O—(CH₂)_(m)CON(R)₂, wherein the groups bound to the nitrogen atom may be in the Z- or E-configuration; R¹ and R² are independently hydrogen or halogen; and R⁹ and R¹⁰ are independently hydrogen or aliphatic.
 8. A pharmaceutical composition comprising particles comprising an effective HSP 90-inhibiting amount of a compound of claim 1, in combination with a pharmaceutically acceptable carrier.
 9. A pharmaceutical composition comprising particles comprising an effective kinase-inhibiting amount of a compound of claim 1, in combination with a pharmaceutically acceptable carrier.
 10. The pharmaceutical composition of claim 8, wherein the particles are less than about 2 microns average particle size.
 11. The pharmaceutical composition of claim 9, wherein the particles are less than about 2 microns average particle size.
 12. The pharmaceutical composition of claim 8, wherein the carrier is suitable for oral, parenteral, inhalation, topical, or intradermal administration.
 13. The pharmaceutical composition of claim 9, wherein the carrier is suitable for oral, parenteral, inhalation, topical, or intradermal administration.
 14. A pharmaceutical composition comprising an effective HSP 90-inhibiting amount of a compound of claim 1, in combination or alternation with another active agent and with a pharmaceutically acceptable carrier.
 15. A pharmaceutical composition comprising an effective kinase-inhibiting amount of a compound of claim 1, in combination or alternation with another active agent and with a pharmaceutically acceptable carrier.
 16. The compound of claim 1, wherein R⁷ is —OH.
 17. The compound of claim 1, wherein the compound has the following structure:


18. The compound of claim 1, wherein the compound has the following structure:


19. The compound of claim 1, wherein the compound has the following structure: 